Biology subjects

Lyu, D.

Publications and source records attributed to Lyu, D..

9 recordsLinked to original sources

bioRxiv2026

Diffusion MRI Tractography Predicts Electrophysiological Connectivity and Explains Spectral Signatures of Evoked Potentials in the Human Brain

White matter fiber bundles are the structural conduits of information flow in the human brain and thereby mediate the spatial trajectories and timings of the electrophysiological signaling. Here, we combined diffusion magnetic resonance imaging (dMRI) and stereoelectroencephalography (SEEG) recordings in neurosurgical patients to develop an integrated framework for predicting and interpreting causal electrophysiological connectivity patterns between pairs of brain regions. We used repeated single-pulse electrical stimulation in 40 participants implanted with a total of 5794 intracranial electrodes throughout the human brain, encompassing both cortical and multiple thalamic nuclei. A nonlinear, time-frequency manifold learning approach was used to define electrophysiological connectivity, which was then compared with subject-specific and atlas-based structural connectivity. Across 150,000 electrode pairs, we found that the presence of a structural connection predicted causal electrophysiological connectivity with a probability of ~0.95; and its absence predicted the lack of the direct electrophysiological connectivity with a probability of ~0.8. We also show evidence of indirect/polysynaptic pathways supported by both modalities and reported neural features from time-frequency decomposition that distinguished between direct and indirect signaling. We demonstrated that an early phase-locked broadband component (10-70 ms) marked direct structural pathways, whereas delayed and slower components reflected indirect propagation. Notably, we reported that thalamic involvement within an indirect pathway results in increased latency (> 200 ms) and enhanced late oscillatory behavior, despite increased conduction velocity measures along thalamo-cortical pathways. Therefore, our multimodal framework maps human brain connectivity, bridging structural architecture, causal electrophysiological dynamics, and network-level communication.

neuroscience↗

bioRxiv2026

Thalamocortical orchestration of human theory of mind

Reasoning about others thoughts or beliefs is central to human social behavior. This ability, known as theory of mind (ToM), has been primarily attributed to cortical regions of the default network (DN). However, whether and how subcortical structures, particularly the thalamus, contribute to this high-level computation remains unknown. Here, we investigated human thalamocortical dynamics during a naturalistic ToM movie watching condition, taking a rare dual-modality approach by combining high-field 7T fMRI and intracranial stereoelectroencephalography (sEEG). Across both modalities, ToM events reliably activated the DN, whereas the thalamus lacked canonical local activation. Despite this absence of local activation, the thalamus shared ToM-related representational structure and exhibited enhanced bidirectional interactions with the DN during mentalizing across methods. Crucially, sEEG revealed that the thalamus coordinated DN activity via cross-frequency phase-amplitude coupling (PAC), whereby thalamic low-frequency phase unidirectionally modulated DN high-frequency activity. Furthermore, the strength of thalamic-DN PAC predicted both the activity magnitude and the representational quality of ToM-related information within the dorsomedial DN subsystem. Together, these findings identify the human thalamus as a regulatory hub that gates DN computations during ToM without exhibiting observable localized activity, revealing a previously unrecognized mechanism by which thalamic dynamics coordinate high-level social cognition in humans.

neuroscience↗

bioRxiv2026

Targeting phosphodiesterase 10A disrupts MAPK signaling pathways in the tumor microenvironment to unleash antitumor immunity

Phosphodiesterase 10A (PDE10A), a cyclic nucleotide-degrading enzyme, is overexpressed in various human cancers. While PDE10A inhibition using small-molecule inhibitors or gene silencing suppresses tumor growth in xenograft models, its precise mechanism of action and immunological impact remain unclear. Here, we report that ADT-030, a novel PDE10A inhibitor, exhibits potent cytotoxicity against a broad range of murine tumor cell lines. ADT-030 is orally bioavailable and effectively suppresses tumor growth across multiple syngeneic mouse models. Notably, its efficacy is diminished in immunodeficient mice or upon CD8+ T cell depletion, highlighting a critical dependence on host immunity. The immunostimulatory properties of ADT-030 are further supported by its ability to induce immunogenic tumor cell death and promote dendritic cell (DC) maturation, its reliance on Batf3-expressing DCs to elicit antitumor CD8+ T cell response, and its synergy with anti-PD-1 therapy. Comprehensive immune profiling in the 4T1 breast cancer model, both in orthotopic and metastatic settings, revealed that ADT-030 selectively reduces myeloid-derived suppressor cells (MDSCs) while normalizing the immune landscape within the tumor. Mechanistically, ADT-030 disrupts multiple components of the mitogen-activated protein kinase (MAPK) signaling network in both tumor cells and MDSCs, leading to induction of apoptosis in these populations. These findings highlight the multi-faceted impact of PDE10A inhibition as a therapeutic strategy that not only disrupts tumor-intrinsic oncogenic signaling to inhibit tumor progression but also reshapes the tumor immune microenvironment to unleash antitumor immunity.

immunology↗

bioRxiv2026

Divergent Electrophysiological Responses in the Human Hippocampus During Verbal Memory Processing

The profile of electrophysiological responses in the human hippocampus (HPC) during verbal memory processing has remained complex and unclear. Here, we studied 26 patients implanted with intracranial electrodes across 187 HPC sites (50% left, 2-18 per patient). During memory encoding and retrieval, a subset of HPC responsive sites demonstrated increased ripple events, along with elevated high-frequency (HFA >50 Hz), and low-frequency (LFA 1-8 Hz) activity. A nearly equal number of sites showed no changes in ripple rate but increased LFA power and a delayed response-locked decrease in HFA power. More importantly, both successful encoding as well as recognition of remembered words were strongly associated with the coordination of the timing of LFA and HFA increases across the two clusters of responsive HPC sites. Using direct cortical electrical stimulations, we confirmed overlapping, but partially distinct, cortical connections to the functionally distinct HPC clusters. Our findings suggest a mesoscale mosaic functional organization within the human HPC where adjacent sites with divergent electrophysiological responses may have specialized roles during verbal memory processing. More importantly, our findings suggest that successful human memory depends on the coordination of the timing of low and high frequency local fields generated across these functionally divergent neuronal population sites.

neuroscience↗

bioRxiv2025

Electrophysiological Brain Connectivity and Subjective States Evoked by Electrical Stimulation of the Human Mediodorsal Thalamus

Recent advances in human intracranial EEG (iEEG) have enabled new investigations into the role of the thalamus in human brain functions. In this study, we applied direct intracranial electrical stimulation (iES) to the mediodorsal (MD) subregion of the thalamus using both high-frequency (50 Hz, iESHF) and low-frequency (0.5 Hz, iESLF) procedures to examine its impact on conscious experience and causal brain connectivity in 30 patients with focal refractory epilepsy (128 electrode contacts; 4 {+/-} 1 MD sites per patient). iESHF of the MD elicited reportable changes in conscious experience in 11 of 12 patients (39 sites; 83 stimulations across 27 unique pairs) - predominantly in the visceral, emotional, or somatosensory domains and often described as unpleasant without any lateralization effect. Our connectivity analyses based on iESLF revealed that the cingulate and insular cortices produced stronger electrophysiological responses in the MD (inflow connectivity) than did the sites in the prefrontal cortex (PFC) within the same individuals. Moreover, MD stimulation showed its strongest outflow connectivity to the cingulate, insular, and PFC regions, all significantly stronger than to medial temporal lobe (MTL) structures. Notably, inflow from both MTL and insula sites to the MD were significantly stronger than their reverse directions, indicating clear asymmetry in connectivity. These findings provide direct evidence that stimulation of the human thalamus can modulate conscious experience. They also highlight the extensive bidirectional connectivity between the MD and cingulate and insular cortices along with asymmetric connectivity between the MD and MTL and insula sites in the human brain. SIGNIFICANCE STATEMENTOur findings provide a functional and causal map of the mediodorsal thalamus (MD) in the human brain. We provide direct evidence that stimulation of the human thalamus can modulate conscious experience. This study also holds clinical and translational value for identifying thalamic pathways involved in the propagation and generalization of seizures, especially seizures involving the medial temporal lobe, as well as for neuromodulation in epilepsy and other neuropsychiatric disorders, as MD stimulation may not be well-tolerated in human subjects.

neuroscience↗

bioRxiv2024

Diminished functional gradient of the precuneus during altered states of consciousness

The relationship between the default mode network (DMN) and task-positive networks, such as the frontoparietal control network (FPCN), is a prominent feature of functional connectivity (FC) in the human brain. This relationship is primarily anticorrelated at rest in healthy brains and is disrupted in altered states of consciousness. Although the DMN and FPCN seem to perform distinct and even opposing roles, they are anatomically adjacent and exhibit ambiguous boundaries. To test the hypothesis that the DMN-FPCN distinction manifests probabilistically rather than having absolute anatomical boundaries, we examined the differences in FC along the dorsal-ventral (d-v) axis in the posterior precuneus (PCu), which serves a convergence zone between the DMN and FPCN. Our findings indicate that the connectivity differences along this axis are continuous as characterized by linear slopes. Notably, these linear relationships (i.e., functional gradients of the precuneus/FGp) are present only within the territories of the DMN and FPCN, respectively associating with positive and negative slopes. Furthermore, the gradient is functionally relevant, as its spatial configurations change in specific ways in altered states of consciousness (ASC): the magnitude of FGp is similarly impaired across different types of ASC, while the spatial entropy of FGp differs between psychedelic and sedative states. These results suggest that the DMN and FPCN, while appearing distinct, may originate from a single, integrated mechanism. Significance StatementThis research provides new insights into the brains functional organization underlying human conscious states by examining the relationship between two large-scale networks: the default mode network (DMN) and the frontoparietal control network (FPCN). These networks, which are attuned to handle internal and external information respectively, are often viewed as oppositional. However, our findings indicate they form an integrated system with continuous connectivity. We identified the posterior precuneus as a key convergence point, revealing a gradient of connectivity between the two networks. This gradient flattens during altered states of consciousness induced by psychedelics or sedatives, showing a loss of functional differentiation between the DMN and FPCN.

neuroscience↗

bioRxiv2024

An Unbiased Proteomic Platform for Activity-based Arginylation Profiling

Protein arginylation is an essential posttranslational modification (PTM) catalyzed by arginyl-tRNA-protein transferase 1 (ATE1) in mammalian systems. Arginylation features a post-translational conjugation of an arginyl to a protein, making it extremely challenging to differentiate from translational arginine residues with the same mass in a protein sequence. Here we present a general ATE1-based arginylation profiling platform for the unbiased discovery of arginylation substrates and their precise modification sites. This method integrates isotopic arginine labeling into an ATE1 assay utilizing biological lysates (ex vivo) rather than live cells, thus eliminating translational bias derived from the ribosomal activity and enabling bona fide arginylation identification using isotopic features. The method has been successfully applied to an array of peptide, protein, cell, patient, and animal tissue samples using 20 {micro}g sample input, with 235 unique arginylation sites revealed from human proteomes. Representative sites were validated and followed up for their biological functions. The developed platform is globally applicable to the aforementioned sample types and therefore paves the way for functional studies of this difficult-to-characterize protein modification.

biochemistry↗

bioRxiv2024

A thalamic perspective of (un)consciousness in pharmacological and pathological states in humans

Currently, there is substantial ongoing discussion around the functional role of the thalamus in consciousness. What is missing in the literature, however, is a systematic investigation of the relevance of specific thalamic nuclei in pharmacologically and pathologically altered states of consciousness in humans. Using functional neuroimaging in both healthy anaesthetised volunteers and patients with disorders of consciousness (DOC), we sought to identify which specific thalamic subregions in both cohorts may be differentially significant for loss of consciousness. Our findings revealed that the pulvinar (Pu) and ventral-latero-ventral (VLV) nuclei, in anaesthesia, and the VLV, in DOC, had distinct functional connectivity patterns related to the default mode and somatomotor networks. Remarkably, among all nuclei, the Pu was found to have the strongest functional connectivity change with anaesthetic-induced loss of consciousness, while in DOC patients, we found the VLV revealed the strongest connectivity change in comparison with healthy controls. Furthermore, we provide evidence that this neural connectivity biomarker in patients also mirrors the changes observed at the behavioural level, which could have clinical implications for targeted deep brain stimulation in therapy for DOC.

neuroscience↗

bioRxiv2024

Distinct roles of Nrf1 and Nrf2 in coordinately controlling the anti-ageing response

Cellular senescence has been accepted as a fundamental contributor to ageing and a variety of age-related diseases, in which oxidative stress has been further recognized to play a critical initiation role. However, the anti-senescence potential of antioxidant nuclear factor erythroid-derived 2-like 1 (Nrf1, encoded by Nfe2l1) remains elusive to date, even though the hitherto accumulating evidence demonstrates that it is an indispensable redox-determining transcription factor for maintaining cellular homeostasis and organ integrity. Herein, we discovered that deletion of Nrf1 resulted in markedly elevated senescence characteristics in Nrf1-/- cells, as characterized by two distinct experimental models induced by oxidative stress, which are evinced by typically heightened activity of senescence-associated {beta}-galactosidase and progressive senescence-associated secretory phenotype (SASP), along with decreased cell vitality and intensified cell cycle arrest. Further experimental investigation also uncovered that such acceleration of oxidative stress-induced senescence resulted from heightened disturbance in the cellular homeostasis, because deficiency of Nrf1 leads to the STAG2- and SMC3-dependent chromosomal stability disruption and autophagy dysfunction, though as accompanied by excessive accumulation of Nrf2 (encoded by Nfe2l2). The aberrant hyperactive Nrf2 cannot effectively counteract the escalating disturbance of cellular homeostasis caused by Nrf1-/-. Overall, this study has provided a series of evidence supporting that Nrf1 indeed exerts an essential protective function against oxidative stress-induced cellular senescence, thereby, highlighting its primary indispensable contribution to maintaining robust cell homeostasis.

biochemistry↗