Biology subjects

chen, l.

Publications and source records attributed to chen, l..

5 recordsLinked to original sources

bioRxiv2025

End-to-end single-stranded DNA sequence design with all-atom structure reconstruction

Designing biological sequences that fold into predefined conformations is a central challenge in bioengineering. Although deep learning has enabled significant advances in protein and RNA sequence design, progress in single-stranded DNA (ssDNA) design has been constrained by the limited availability of structural data. To address this challenge, we introduce InvDNA, a deep learning-based method that designs ssDNA sequences directly from backbone atomic coordinates. This end-to-end formulation avoids the loss of structural information during backbone-to-feature conversion and further accommodates flexible backbone representations, dynamic sequence masking, and structural reconstruction objectives. These strategies bolster InvDNAs ability to generalize across diverse ssDNA structural contexts while enabling additional functionalities, including generating diverse sequences for a given backbone, reconstructing nucleotide conformations from backbone and preserving functional sites. In benchmarks using experimentally determined ssDNA structures, InvDNA demonstrates more than a twofold improvement in sequence recovery compared with existing ssDNA and RNA sequence design approaches. Further computational validation using AlphaFold3 shows that 44.4% of InvDNA-designed sequences successfully fold into their predefined conformations. Notably, this success rate increases when backbone coordinates are perturbed to diversify the InvDNA-designed sequences. Collectively, these results establish InvDNA as a robust framework for rational ssDNA engineering.

molecular biology↗

bioRxiv2025

Slow synaptic plasticity from the hippocampus underlies gradual mapping and fragmentation of novel spaces by grid cells

Animals construct internal "cognitive maps" of the world during navigation in spatial and non-spatial domains, with grid cells in the medial entorhinal cortex (MEC) playing a key role. This requires associating internal position estimates with external cues to reduce spatial uncertainty over time. However, how grid cell representations evolve in novel spaces to support map formation is unclear. To address this question, we longitudinally imaged calcium dynamics of grid cells over 10 days as mice learn operant tasks in novel virtual linear tracks. We observe that spatial tuning of grid cells is present immediately in novel tracks but evolves as a significant fraction of spatial fields shift backward on a run-by-run basis, within and across days. Backward shifts are more prevalent and persistent in successful learners. The fields gradually stabilize across days, anchored by landmarks, suggesting slow plasticity. The backward shifts partially reset daily, reflecting a slower consolidation timescale. While individual fields of a cell shift differentially, co-active fields of co-modular grid cells shift together, indicating their coupled dynamics on the same two-dimensional torus. Spatial learning leads to systematic changes and stabilization of their population phase trajectory, including lateral shift, rotation, and phase resets at landmarks, forming a landmark-fragmented representation for the environment. Next, we build an entorhinal-hippocampal model that provides a mechanistic explanation of the diverse phenomena - grid field shifts, increasing fidelity, and fragmentation of the spatial map - and predicts slow Hebbian plasticity in the hippocampus-to-entorhinal pathway. Supporting this, electrophysiology demonstrates that learning-performance-correlated weakening of local inhibition facilitates potentiation of indirect hippocampal inputs to superficial MEC. Together, our study provides multifaceted evidence of slow hippocampus-to-MEC plasticity, elucidating the formation of stable and fragmented cognitive maps that combine internal and cue-driven positional estimates in rich environments during learning. This mechanism may extend to broader memory processes involving this circuit.

neuroscience↗

bioRxiv2025

Distinct mechanisms are employed by T-cell-instructed myeloid cells for IL-1β production in humans and mice.

Interleukin-1 beta (IL-1{beta}) is known as an inflammasome-dependent pro-inflammatory cytokine that has been implicated in T-cell-driven autoimmune diseases. In mice, T-cells were reported to instruct myeloid cells to produce IL-1{beta} via an inflammasome-independent mechanism, that engages TNFR and Fas-caspase-8-dependent signalling pathways. In this study, we explored T-cell-driven myeloid IL-1{beta} production in humans. Co-culturing of autologous primary T-cells (memory CD4+ and CD8+) with myeloid cells (monocyte, macrophage and dendritic cells) revealed that both memory CD4+ and CD8+ T cells induce IL-1{beta} secretion. Also, caspase-1 rather than caspase-8 cleaves pro-IL-1{beta} in human myeloid cells. This process depends on TNF-, CD40L and IFN-{gamma} together rather than TNF- alone, leading to upregulated pro-IL-1{beta} expression in human myeloid cells. We additionally show that TNF-, CD40L and IFN-{gamma} independently enhance IL-1{beta} secretion. Together, our study highlights that, despite the shared biology in T-cell-instructed IL-1{beta} production between humans and mice, different underlying molecular pathways are implicated. SummaryLike murine cells, human T-cells stimulate IL-1{beta} secretion from myeloid cells. However, the underlying mechanisms differ, with IL-1{beta} production in humans being driven by TNF-, CD40L, IFN-{gamma}, and Caspase-1, whereas in mice, it is primarily regulated by TNF- and Caspase-8.

immunology↗

bioRxiv2025

Single-Cell Sequencing Identifies the Crucial Role of Mitochondrial Fission-Fusion Balance in Cardiac Hypertrophy Progression

BackgroundThe heart undergoes growth in response to both pathological and physiological stimuli. Pathological hypertrophy often leads to cardiomyocyte loss and heart failure (HF), whereas physiological hypertrophy paradoxically protects the heart and enhances cardiomyogenesis. The molecular mechanisms that distinguish these two forms of hypertrophy remain unclear. MethodsIn this study, we utilized single-cell transcriptomics from transverse aortic constriction (TAC) models at 2, 5, 8, and 11 weeks (GSE120064), along with bulk RNA sequencing from mice subjected to 12 months of exercise-induced physiological hypertrophy and cardiomyogenesis (CRA007207), to investigate the molecular differences between pathological and physiological hypertrophy. ResultsOur results reveal the following. Mitochondrial-related pathways are the primary drivers of the pathological changes that occur following TAC. The mitochondrial fission and fusion pathways exhibited increased activity at 2 weeks but decreased activity at 5, 8, and 11 weeks post TAC. The expression pattern of exercise-induced physiological hypertrophy was similar to that of 2-week TAC-induced changes, indicating that the early stage of TAC represents an adaptive physiological response or physiological hypertrophy. Notably, during HF, the fission genes Fis1 and Dnm1l increase, in contrast to the expected decrease in fusion genes. These findings were experimentally validated, indicating that the mitochondrial fission genes Fis1 and Dnm1l are key promoters of HF. ConclusionsOur data indicate that the balance between mitochondrial fission and fusion plays a critical role in the transition from physiological to pathological hypertrophy. The fission-related genes Fis1 and Dnm1l have emerged as key drivers of pathological hypertrophy and heart failure. These findings suggest that targeting fission genes, particularly Fis1 and Dnm1l, may represent promising therapeutic strategies for managing heart failure.

bioinformatics↗

bioRxiv2024

Human DDIT4L intron retention contributes to cognitive impairment and amyloid plaque formation.

Cognitive impairment and amyloid plaques are the most important clinical and neuropathological feature for dementia, especially in Alzheimers disease (AD). However, the etiology of dementia is complicated. The present study reveals that an aberrant splicing of DDIT4L, the isoform DDIT4L intron retention (DIR), occurs in AD patients. Homozygous DIR-knock-in (KI) mice showed DIR expression in hippocampal neurons, marked cognitive impairment, augmented A{beta} deposition and enhanced Tau phosphorylation. The DIR colocalized with thioflavin S-positive plaques and gelsolin in AD patients. The DIR induced A{beta} deposition and cognitive impairment by interacting with gelsolin. Moreover, DIR interacted with GluA1, the subunit of the AMPA receptor, contributing to synaptic deficiency and cognitive impairment. Furthermore, an anti-DIR monoclonal antibody (mAb) alleviated cognitive impairment and reduced A{beta} deposition and Tau phosphorylation. Thus, DIR contributes to cognitive impairment and amyloid plaques, and could be a potential therapeutic target for dementia.

neuroscience↗