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Song, H.

Publications and source records attributed to Song, H..

At least 127 records · Page 7Linked to original sources

High performers demonstrate greater neural synchrony than low performers across behavioral domains

Heterogeneity in brain activity gives rise to heterogeneity in behavior, which in turn comprises our distinctive characteristics as individuals. Studying the path from brain to behavior, however, often requires making assumptions about how similarity in behavior scales with similarity in brain activity. Here, we expand upon recent work which proposes a theoretical framework for testing the validity of such assumptions. Using intersubject representational similarity analysis in two independent movie-watching fMRI datasets, we probe how brain-behavior relationships vary as a function of behavioral domain and participant sample. We find evidence that, in some cases, the neural similarity of two individuals is not correlated with behavioral similarity. Rather, individuals with higher behavioral scores are more similar to other high scorers whereas individuals with lower behavioral scores are dissimilar from everyone else. Ultimately, our findings motivate a more extensive investigation of both the structure of brain-behavior relationships and the tacit assumption that people who behave similarly will demonstrate shared patterns of brain activity.

neuroscience↗

Hypoxia Bi-directionally Regulates Gut Vascular Barrier through HIF-1α-dependent Mechanism in vitro

ObjectiveThe gut vascular barrier (GVB) is the key checkpoint for pathogens to enter the blood circulation through the intestine, which is crucial for maintaining the intestinal barrier function. However, the effect and molecular mechanism of hypoxia on GVB remains unclear. Here, we show a role of the transcription factor hypoxia inducible factor-1 (HIF-1) in hypoxia-induced bi-directional regulation of GVB. Approach and ResultsAn in vitro GVB model composed of rat intestinal microvascular endothelial cells was studied. Evans blue-albumin efflux assay showed that the experimentally severe hypoxia induced by cobalt chloride (500 M, 24 h) markedly disrupted the GVB in vitro, while mild hypoxia induced by cobalt chloride (500 M, 6 h) evidently enhanced the GVB, revealing hypoxia-induced bi-directional regulation of the GVB for the first-time. Importantly, knockdown of HIF-1 largely abolished the bi-directional changes of GVB caused by hypoxia. Furthermore, experimentally severe hypoxia exacerbated the inflammatory GVB disruption induced by LPS or TNF-, while the mild hypoxia promoted the repair. ConclusionCollectively, our data indicate that hypoxia bi-directionally regulates GVB in a HIF-1-dependent manner.

cell biology↗

Coupling of Slack and NaV1.6 sensitizes Slack to quinidine blockade and guides anti-seizure strategy development

Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidines blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6s N-and C-termini binding to Slacks C-terminus, and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slacks C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of "Slack as an isolated target" for anti-epileptic drug discovery efforts, and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/532982v3_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1127858org.highwire.dtl.DTLVardef@19ad9f4org.highwire.dtl.DTLVardef@15b5542org.highwire.dtl.DTLVardef@13a86b4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Single-Soma Deep RNA sequencing of Human DRG Neurons Reveals Novel Molecular and Cellular Mechanisms Underlying Somatosensation

The versatility of somatosensation arises from heterogeneous dorsal root ganglion (DRG) neurons. However, soma transcriptomes of individual human DRG (hDRG) neurons - critical information to decipher their functions - are lacking due to technical difficulties. Here, we developed a novel approach to isolate individual hDRG neuron somas for deep RNA sequencing (RNA-seq). On average, >9,000 unique genes per neuron were detected, and 16 neuronal types were identified. Cross-species analyses revealed remarkable divergence among pain-sensing neurons and the existence of human-specific nociceptor types. Our deep RNA-seq dataset was especially powerful for providing insight into the molecular mechanisms underlying human somatosensation and identifying high potential novel drug targets. Our dataset also guided the selection of molecular markers to visualize different types of human afferents and the discovery of novel functional properties using single-cell in vivo electrophysiological recordings. In summary, by employing a novel soma sequencing method, we generated an unprecedented hDRG neuron atlas, providing new insights into human somatosensation, establishing a critical foundation for translational work, and clarifying human species-specific properties.

neuroscience↗

Endothelial cell-derived lactate triggers mesenchymal stem cell histone lactylation to attenuate osteoporosis

Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism is unclear. The present study found that ovariectomized mice exhibit reductions in bone blood vessel density and expression of endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Additional data showed that endothelial cell (EC)-specific deletion of Pkm2 impair osteogenesis and worsen osteoporosis in mice. This was attributed to the impaired differentiation ability toward osteoblast of bone mesenchymal stem cells (BMSCs). Mechanistically, EC-specific deletion of Pkm2 reduce serum lactate levels secreted by ECs, which affect histone lactylation of BMSCs. We identified collagen type I alpha 2 chain, cartilage oligomeric matrix protein, ectonucleotide pyrophosphatase/phosphodiesterase 1, and transcription factor 7 like 2 as histone H3K18 lactylation-regulated osteogenic genes using joint CUT&Tag and RNA-sequencing analyses. The overexpression of PKM2 in ECs, addition of lactate, and exercise were observed to restore the phenotype of endothelial Pkm2-deficient mice. Furthermore, metabolomics of the serum indicated that osteoporosis patients showed a relatively low lactate level. The histone lactylation and related osteogenic genes of BMSCs in osteoporosis patients also decreased. In conclusion, the glycolysis of ECs fuels the differentiation of BMSCs into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis through increased serum lactate.

cell biology↗

Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function

Dopamine system dysfunction is commonly implicated in adolescent-onset neuropsychiatric disorders. Although psychosis symptoms can be alleviated by antipsychotics, cognitive symptoms remain unresponsive to such pharmacological treatments and novel research paradigms investigating the circuit substrates underlying cognitive deficits are critically needed. The frontal cortex and its dopaminergic input from the midbrain are implicated in cognitive functions and undergo maturational changes during adolescence. Here, we used mice carrying mutations in the Arc or DISC1 genes to model mesofrontal dopamine circuit deficiencies and test circuit-based neurostimulation strategies to restore cognitive functions. We found that in a memory-guided spatial navigation task, frontal cortical neurons were activated coordinately at the decision-making point in wild-type but not Arc mutant mice. Chemogenetic stimulation of midbrain dopamine neurons or optogenetic stimulation of frontal cortical dopamine axons in a limited adolescent period consistently reversed genetic defects in mesofrontal innervation, task-coordinated neuronal activity, and memory-guided decision-making at adulthood. Furthermore, adolescent stimulation of dopamine neurons also reversed the same cognitive deficits in DISC1 mutant mice. Our findings reveal common mesofrontal circuit alterations underlying the cognitive deficits caused by two different genes and demonstrate the feasibility of adolescent neurostimulation to reverse these circuit and behavioral deficits. These results may suggest developmental windows and circuit targets for treating cognitive deficits in neurodevelopmental disorders.

neuroscience↗

RabbitVar: ultra-fast and accurate somatic small-variant calling on multi-core architectures

The continuous development of next-generation sequencing (NGS) technology has led to extensive and frequent use of genomic analysis in cancer research. The associated production of large-scale NGS datasets establishes the need for high-precision somatic variant calling methods that are highly optimized on commonly used hardware platforms. We present RabbitVar (https://github.com/LeiHaoa/RabbitVar), a scalable variant caller that can detect small somatic variants from paired tumor/normal NGS data on modern multi-core CPUs. Our approach combines candidate-finding and machine-learning-based filtering strategies with optimized data structures and multi-threading to achieve both high accuracy and efficiency. We have compared the performance of RabbitVar to leading state-of-the-art callers (Strelka2, Mutect2, NeuSomatic, VarDict, VarScan2) on real-world HCC1395 breast cancer datasets under different sequencing conditions and contamination rates. The evaluation results demonstrate that RabbitVar achieves highly competitive F1-scores when calling SNVs. Moreover, when calling the more challenging indel variants, it consistently achieves the highest F1-scores. RabbitVar is able to process a paired tumor and normal whole human genome sequencing datasets with 80x depth in less than 20 minutes on a 48-core workstation outperforming all other tested variant callers in terms of efficiency.

bioinformatics↗

NSC-derived exosomes enhance therapeutic effects of NSC transplantation on cerebral ischemia in mice

AbstractTransplantation of neural stem cells (NSCs) has been proved to promote functional rehabilitation of brain lesions including ischemic stroke. However, the therapeutic effects of NSC transplantation is limited by the low survival and differentiation rates of NSCs due to the harsh environment in the brain after ischemic stroke. Here, we employed NSCs derived from human induced pluripotent stem cells (iPSCs) together with exosomes extracted from NSCs to treat cerebral ischemia induced by middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. The results showed that NSC-derived exosomes significantly reduced the inflammatory response, alleviated oxidative stress after NSC transplantation, and facilitated NSCs differentiation in vivo. The combination of NSCs with exosomes ameliorated the injury of brain tissue including cerebral infarct, neuronal death and glial scarring, and promoted the motor function recovery. To explore the underlying mechanisms, we analyzed the miRNA profiles of NSC-derived exosomes and the potential downstream genes. Our study provided the rationale for the clinical application of NSC-derived exosomes as a supportive adjuvant for NSC transplantation after stroke.

neuroscience↗

Large-scale neural dynamics in a shared low-dimensional state space reflect cognitive and attentional dynamics

Cognition and attention arise from the adaptive coordination of neural systems in response to external and internal demands. The low-dimensional latent subspace that underlies large-scale neural dynamics and the relationships of these dynamics to cognitive and attentional states, however, are unknown. We conducted functional magnetic resonance imaging as human participants performed attention tasks, watched comedy sitcom episodes and an educational documentary, and rested. Whole-brain dynamics traversed a common set of latent states that spanned canonical gradients of functional brain organization, with global synchrony among functional networks modulating state transitions. Neural state dynamics were synchronized across people during engaging movie watching and aligned to narrative event structures. Neural state dynamics reflected attention fluctuations such that different states indicated engaged attention in task and naturalistic contexts whereas a common state indicated attention lapses in both contexts. Together, these results demonstrate that traversals along large-scale gradients of human brain organization reflect cognitive and attentional dynamics.

neuroscience↗

Non-viral gene editing in utero with lipid nanoparticles complexed to mRNA

Nanoparticle-based drug delivery systems have the potential to revolutionize medicine but their low vascular permeability and rapid clearance by phagocytic cells have limited their medical impact. Nanoparticles delivered at the in utero stage have the potential to overcome these key limitations, due to the high rate of angiogenesis and cell division in fetal tissue, and the under-developed immune system. However, very little is known about nanoparticle drug delivery at the fetal stage of development. In this report, using Ai9 CRE reporter mice, we demonstrate that lipid nanoparticle (LNP) mRNA complexes can deliver mRNA for gene editing enzymes in utero after an intrahepatic injection, and can access and edit major organs, such as the heart, the liver, kidneys, lungs and the gastrointestinal tract with remarkable efficiency and low toxicity. In addition, we show here that Cas9 mRNA and sgRNA complexed to LNPs were able to edit the fetal organs in utero after an intrahepatic injection. These experiments demonstrate the possibility of non-viral delivery of gene editing enzymes in utero and nanoparticle drug delivery has great potential for delivering macromolecules to organs outside of the liver in utero, which provides a promising strategy for treating a wide variety of devastating genetic diseases before birth.

genetics↗

A new species of Nanhsiungchelys (Testudines: Cryptodira: Nanhsiungchelyidae) from the Upper Cretaceous of Nanxiong Basin, China, and the role of anterolateral processes on the carapace in drag reduction

Nanhsiungchelyidae are a group of large turtles that lived in Asia and North America during the Cretaceous. Here we report a new species of nanhsiungchelyid, Nanhsiungchelys yangi sp. nov., from the Upper Cretaceous of Nanxiong Basin, China. This is the second valid species of Nanhsiungchelys, and the holotype consists of a well-preserved skull and lower jaw, as well as the anterior parts of the carapace and plastron. The diagnostic features of Nanhsiungchelys include a huge estimated body size (~55.5 cm), a special network of sculptures on the surface of the skull and shell, weak cheek emargination and temporal emargination, deep nuchal emargination, and a pair of anterolateral processes on the carapace. However, Nanhsiungchelys yangi differs from the other species of Nanhsiungchelys in having a triangular-shaped snout and wide anterolateral processes. A phylogenetic analysis of nanhsiungchelyids places Nanhsiungchelys yangi and Nanhsiungchelys wuchingensis as sister taxa. Some nanhsiungchelyids bear special anterolateral processes on the carapace, which are unknown in extant turtles. Here we test the function of these processes in Nanhsiungchelys yangi using computational fluid dynamics, and the results suggest these processes could enhance locomotory performance by remarkably reducing drag force when the animal was swimming through water.

paleontology↗

Practical scan-length considerations for mapping upper limb movements to the somatosensory/motor cortex at 7T

The relationship between motor cortex (M1) and upper limb movements has been investigated extensively using functional MRI (fMRI). While most research has focused on applications, very few studies have focused on practical aspects related to developing the fMRI protocol. Thus, the effect of scan length on M1 activations during various upper limb movements remains unclear. Scan length constraints are important for conducting motor experiments within a 60- or 90-min scan session. We targeted this gap by studying 7T fMRI activations in a male participant while performing eight different upper limb movements (of the fingers, wrist, and elbow) across 16 task runs (8 with the left arm, 8 with the right arm, 88 mins total fMRI duration). Standard activation analyses were performed (Z>3.1, p<0.01, cluster thresholded) independently for 14 different cases (2 runs through 8 runs, left and right arm) and compared. We found diminishing returns with higher number of runs (activations gradually plateaued with runs). We observed two clusters of movements, one with generally higher activation (more activated voxels and higher Z-stats) and the other with lower activation. To achieve similar statistical power, movements with lower activation required longer scanning (more runs). Based on these observations, we propose a one size does not fit all practical protocol within a 60-, 75-, or 90-min scan session, wherein different number of runs are assigned for different movements. Our study could benefit researchers who are designing upper limb fMRI experiments.

neuroscience↗

Global remapping in granule cells and mossy cells of the mouse dentate gyrus

Hippocampal place cells exhibit spatially modulated firing, or place fields, which can remap to encode changes in the environment or other variables. Unique among hippocampal subregions, the dentate gyrus (DG) has two excitatory populations of place cells, granule cells and mossy cells, which are among the least and most active spatially modulated cells in the hippocampus, respectively. Previous studies of remapping in the DG have drawn different conclusions about whether granule cells exhibit global remapping and contribute to the encoding of context specificity. By recording granule cells and mossy cells as mice foraged in different environments, we found that by most measures, both granule cells and mossy cells remapped robustly but through different mechanisms that are consistent with firing properties of each cell type. Our results resolve the ambiguity surrounding remapping in the DG and suggest that most spatially modulated granule cells contribute to orthogonal representations of distinct spatial contexts.

neuroscience↗

Inferring protein fitness landscapes from laboratory evolution experiments

Directed laboratory evolution applies iterative rounds of mutation and selection to explore the protein fitness landscape and provides rich information regarding the underlying relationships between protein sequence, structure, and function. Laboratory evolution data consist of protein sequences sampled from evolving populations over multiple generations and this data type does not fit into established supervised and unsupervised machine learning approaches. We develop a statistical learning framework that models the evolutionary process and can infer the protein fitness landscape from multiple snapshots along an evolutionary trajectory. We apply our modeling approach to dihydrofolate reductase (DHFR) laboratory evolution data and the resulting landscape parameters capture important aspects of DHFR structure and function. We use the resulting model to understand the structure of the fitness landscape and find numerous examples of epistasis but an overall global peak that is evolutionarily accessible from most starting sequences. Finally, we use the model to perform an in silico extrapolation of the DHFR laboratory evolution trajectory and computationally design proteins from future evolutionary rounds.

bioinformatics↗

Profile of the somatic mutational landscape in breast tumors from Hispanic/Latina women

Breast cancer causes the most cancer deaths among Hispanic/Latinas (H/L). However, limited tumor-sequencing data from H/L are available to guide treatment. To address this gap, we performed whole-exome sequencing of DNA from 140 HL germline and 146 matched breast tumors and RNA-seq for the tumors. We generated somatic-mutation profiles, identified copy-number alterations (CNAs), and compared results to non-Hispanic White (White) women in The Cancer Genome Atlas. Similar to Whites, PIK3CA and TP53 were the most commonly mutated genes in breast tumors from H/L. We found 4 common COSMIC mutation signatures (1, 2, 3, 13) and signature 16 not previously reported in other breast-cancer datasets. We observed recurrent amplifications in breast-cancer drivers including MYC, FGFR1, CCND1, and ERBB2, and a recurrent amplification on 17q11.2 associated with high KIAA0100 gene expression, implicated in breast-cancer aggressiveness. Expanded research is required to determine how these characteristics of H/L tumors impact treatment response and survival.

cancer biology↗

Molecular basis for the enzymatic macrocyclization of multiply backbone N-methylated peptides

The enzyme OphP is essential for the biosynthesis of the macrocyclic peptide omphalotin A, a dodecamer with 9 backbone N-methylations produced by the wood-degrading fungus Omphalotus olearius. Heterologous expression of OphP and the peptide-precursor protein OphMA in yeast, yields omphalotin A. Thus, Oph P was hypothesized to have a dual function; catalyzing both endoproteolytic release of a peptide intermediate from OphMA, and macrocyclization of the multiply -N-methylated core peptide with concomitant release of a C-terminal follower peptide. In our in vitro activity assays, OphP showed robust endoproteolytic and macrocyclase activity on -N-methylated peptides but was unable to cleave OphMA. The enzyme had a strong preference for hydrophobic, highly -N-methylated peptides and an -N-methylated glycine residue at the P1 site. OphP adopts a canonical prolyl oligopeptidase (POP) fold with a predominantly hydrophobic substrate binding cleft, and a small and hydrophobic P1 binding pocket. We demonstrate that OphP is a POP-type macrocyclase with a specificity and a substrate route to the active site different from other members of the family. These results could be exploited for the biotechnological production of macrocyclic peptides with multiple backbone N-methylations, which are interesting due to their favorable pharmacological properties.

biochemistry↗

Comprehensive characterization of the transcriptional response to COVID-19 in multiple organs reveals shared signatures across tissues

Infection by Coronavirus SARS-CoV2 is a severe and often deadly disease that has implications for the respiratory system and multiple organs across the human body. While the effects in the lung have been extensively studied, less is known about COVID-19s cellular impact across other organs. Here we contribute a single-nuclei RNA sequencing atlas comprising six human organs across 20 autopsies where we analyzed the transcriptional changes due to COVID-19 in multiple cell types. Computational cross-organ analysis for endothelial cells and macrophages identified systemic transcriptional changes in these cell types in COVID-19 samples. In addition, analysis of signaling pathways from multiple datasets showed several systemic dysregulations of signaling interaction in different cell types. Altogether, the COVID Tissue Atlas enables the investigation of both cell type-specific and cross-organ transcriptional responses to COVID-19, providing insights into the molecular networks affected by the disease and highlighting novel potential targets for therapies and drug development.

genomics↗

Early microglial response, myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes

The sphingolipids galactosylceramide (GalCer), sulfatide (ST) and sphingomyelin (SM) are essential for myelin stability and function. GalCer and ST are synthesized mostly from C22-C24 ceramides, generated by Ceramide Synthase 2 (CerS2). To clarify the requirement for C22-C24 sphingolipid synthesis in myelin lipid biosynthesis and stability, we generated mice lacking CerS2 specifically in myelinating cells (CerS2{Delta}O/{Delta}O). At 6 weeks of age, normal-appearing myelin had formed in CerS2{Delta}O/{Delta}O mice, however there was a reduction in myelin thickness and the percentage of myelinated axons. Pronounced loss of C22-C24 sphingolipids in myelin of CerS2{Delta}O/{Delta}O mice was compensated by greatly increased levels of C18 sphingolipids. A distinct microglial population expressing high levels of activation and phagocytic markers such as CD64, CD11c, MHC class II, and CD68 was apparent at 6 weeks of age in CerS2{Delta}O/{Delta}O mice, and had increased by 10 weeks. Increased staining for denatured myelin basic protein was also apparent in 6-week-old CerS2{Delta}O/{Delta}O mice. By 16 weeks, CerS2{Delta}O/{Delta}O mice showed pronounced myelin atrophy, motor deficits, and axon beading, a hallmark of axon stress. 90% of CerS2{Delta}O/{Delta}O mice died between 16 and 26 weeks of age. This study highlights the importance of sphingolipid acyl chain length for the structural integrity of myelin, demonstrating how a modest reduction in lipid chain length causes exposure of a denatured myelin protein epitope and expansion of phagocytic microglia, followed by axon pathology, myelin degeneration, and motor deficits. Understanding the molecular trigger for microglial activation should aid the development of therapeutics for demyelinating and neurodegenerative diseases. Main PointsO_LIOligodendrocytes lacking CerS2 produce myelin using sphingolipids with C16/C18 instead of C22/C24 N-acyl chains C_LIO_LIC22/C24 myelin sphingolipids are essential for myelin stability, microglial quiescence, and survival beyond young adulthood C_LI Table of Contents Image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/493337v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1125540org.highwire.dtl.DTLVardef@9aeebdorg.highwire.dtl.DTLVardef@1afbeb4org.highwire.dtl.DTLVardef@11156c2_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗