Biology subjects

Lin, J.-J.

Publications and source records attributed to Lin, J.-J..

7 recordsLinked to original sources

bioRxiv2026

A Sequential Assembly Mechanism for Stable Cdc13 Dimerization on Telomeric DNA

The telomere-binding protein Cdc13 specifically binds to single-stranded telomeric DNA, playing a critical role in telomere protection and length regulation. While extensive biochemical, molecular biological, and genetic studies have shown that Cdc13 can form dimers or oligomers in solution and bind telomeric DNA with high specificity, the dynamic mechanism of its loading onto telomeres is less well characterized. Using two single-molecule methods, single-molecule fluorescence resonance energy transfer (smFRET) and colocalization single-molecule spectroscopy (CoSMoS), we demonstrate that Cdc13 initially loads onto telomeres as a monomer. This is followed by the recruitment of a second monomer, forming a stable Cdc13 dimer on a 12-nucleotide telomeric DNA segment. Although genetic studies suggest that monomeric Cdc13 binding alone is insufficient to maintain telomere length, it underscores the Cdc13 monomers regulatory importance in coordinating telomere synthesis and protection. This monomer-to-dimer transition provides a mechanistic basis for understanding the multi-tasked roles of Cdc13 in telomere replication and protection.

biophysics↗

bioRxiv2024

Hsa_circ_0001304 promotes vascular smooth muscle cell autophagy and neointimal hyperplasia through the YTHDF2/mTOR axis

IntroductionAberrant autophagy in vascular smooth muscle cells (VSMCs) is associated with the progression of cardiovascular diseases. Recently, circular RNAs (circRNAs) have gradually been reported to regulate autophagy in VSMCs. ObjectivesThis study aims to investigate the role of hsa_circ_0001304 in VSMC autophagy and its underlying mechanism. MethodsThe combined use of dual-luciferase reporter gene assay, MeRIP-qRT-PCR, RIP-qRT-PCR, etc., was performed to verify the regulatory axis, hsa_circ_0001304/miR-636/YTHDF2/mTOR. Cell autophagy detection was performed to uncover the role of hsa_circ_0001304 on VSMC autophagy. The mouse carotid artery ligation model was conducted to assess the role of hsa_circ_0001304 on vascular neointimal hyperplasia. ResultsHsa_circ_0001304 acts as a sponge for miR-636, leading to an increase in the protein levels of YTHDF2. Subsequently, the YTHDF2 promotes the degradation of mTOR mRNA by binding to the latters m6A modification sites. Thus, by regulating the miR-636/YTHDF2/mTOR axis, hsa_circ_0001304 activates VSMC autophagy, aggravating neointimal hyperplasia. ConclusionOur findings suggest that autophagy-related hsa_circ_0001304 could serve as a novel therapeutic target for neointimal hyperplasia-related cardiovascular diseases. Including spacesOur study documents a novel VSMC autophagy-related circRNA, namely circ-1304, which activates VSMC autophagy through the miR-636/YTHDF2/mTOR axis, thereby exacerbating neointimal hyperplasia. Targeting autophagy-related circ-1304 may contribute to the treatment of neointimal hyperplasia-associated cardiovascular diseases.

molecular biology↗

bioRxiv2023

Elevated ENO2 Disrupts VSMCs Homeostasis Facilitating the Development of Aortic Dissection

OBJECTIVEAortic dissection (AD) is a dangerous cardiovascular disease. However, its regulatory mechanism remains poorly understood. Autophagy is an important pathway for maintaining cellular homeostasis. Recent studies have shown that glycolysis and autophagy are essential for the development of AD. Elevated glycolysis can promote cells autophagy, but the relationship between the two is unclear. Enolase 2 (ENO2) is a glycolytic enzyme. Here, we investigated whether ENO2 can regulate autophagy in vascular smooth muscle cells (VSMCs) involved in the progression of AD. APPROACH AND RESULTSThe levels of ENO2 and autophagy-related proteins in aortic tissues from AD patients were identified by qRT-PCR, Western blot and IHC. We found that autophagosome clearance was impaired in aortic tissues and positively correlated with elevated ENO2 expression. Furthermore, aortic application of smooth muscle-specific adeno-associated virus (AAV) inhibiting ENO2 expression attenuated the development of AD in mice. in vitro experiments, downregulation of ENO2 partially restored PDGF-BB-induced impairment of autophagic flux, as evidenced by reduced expression of Beclin-1, SQSTM1, LC3BII/I and increased levels of LAMP2 in human aortic vascular smooth muscle cells (HAVSMCs). Similarly, increased levels of ENO2 exacerbated the autophagic dysfunction in HAVSMCs. Mechanistically, ENO2 may block autophagic flux through the ENO2-GAP43-ATF4 pathway and disrupt cellular homeostasis. CONCLUSIONSOur data reveal a perturbing role of ENO2 in the homeostasis of VSMCs, suggesting ENO2 as a potential target for intervention in AD.

molecular biology↗

bioRxiv2018

Stimulation of the posterior cingulate impairs episodic memory encoding

Neuroimaging experiments implicate the posterior cingulate cortex (PCC) in episodic memory processing, making it a potential target for responsive neuromodulation strategies outside of the hippocampal network. However, causal evidence for the role PCC plays in memory encoding is lacking. In patients undergoing seizure mapping, we investigated functional properties of the PCC using deep brain stimulation (DBS) and stereotactic electroencephalography (stereo EEG). These techniques allow precise targeting of deep cortical structures including the PCC, and simultaneous acquisition of oscillatory recordings from neighboring regions such as the hippocampus. We used a free recall experiment in which PCC was stimulated during item encoding period of half of the study lists, while no stimulation was applied during encoding period of the remaining lists. We evaluated if stimulation affected memory and/or modulated hippocampal activity. Results revealed four main findings. (i) Stimulation during encoding impaired memory for early items on the study lists. (ii) Stimulation increased hippocampal gamma band power. (iii) Stimulation-induced gamma power predicted memory impairment. (iv) Functional connectivity between the hippocampus and PCC predicted the degree of stimulation effect on memory. Our findings offer the first causal evidence implicating the PCC in episodic memory encoding. Importantly, results highlight that stimulation targeted outside of the temporal lobe can modulate hippocampal activity with implications on behavior. Furthermore, a-priori measures of connectivity between brain regions within a functional network can be informative in predicting behavioral effects of stimulation. Our findings have significant implications for developing therapie to treat diseases of memory loss and cognitive impairment using DBS.\n\nSignificance StatementCognitive impairment and memory loss are critical public health challenges. Deep brain stimulation (DBS) is a promising tool for developing strategies to ameliorate memory disorders by targeting brain regions involved in mnemonic processing. Using DBS, our study sheds light on the lesser-known role of the posterior cingulate cortex (PCC) in memory encoding. Stimulating the PCC during encoding impairs subsequent recall memory. The degree of impairment is predictedby stimulation-induced hippocampal gamma oscillations and functional connectivity between PCC and hippocampus. Our findings provide the first causal evidence implicating PCC in memory encoding and highlight the PCC as a favorable target for neuromodulation strategies, using a-priori connectivity measures to predict stimulation effects. This has significant implications for developing therapies for memory diseases.

neuroscience↗

bioRxiv2018

Functionally distinct high and low theta oscillations in the human hippocampus

Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4-10-Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in thetas function. To characterize human hippocampal theta, we examined the properties of theta oscillations throughout the anterior-posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observed hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displayed oscillations at ~8-Hz and the precise frequency of these oscillations correlated with the speed of movement, implicating these signals in spatial navigation. We also observed slower ~3-Hz oscillations, but these signals were more prevalent in the anterior hippocampus and their frequency did not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high-and low-theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes.

neuroscience↗

bioRxiv2018

Single neurons in the human entorhinal cortex remap to distinguish individual spatial memories

The entorhinal cortex (EC) is known to play a key role in both memory and spatial navigation. Despite this overlap in spatial and mnemonic circuits, it is unknown how spatially responsive neurons contribute to our ability to represent and distinguish past experiences. Recording from medial temporal lobe (MTL) neurons in subjects performing cued recall of object-location memories in a virtual-reality environment, we identified \"trace cells\" in the EC that remap their spatial fields to locations subjects were cued to recall on each trial. In addition to shifting its firing field according to the memory cue, this neuronal activity exhibited a firing rate predictive of the cued memorys content. Critically, this memory-specific neuronal activity re-emerged when subjects were cued for recall without entering the environment, indicating that trace-cell memory representations generalized beyond navigation. These findings suggest a general mechanism for memory retrieval via trace-cell activity and remapping in the EC.

neuroscience↗

bioRxiv2018

Redefining Nephrotic Syndrome in Molecular Terms: Outcome-associated molecular clusters and patient stratification with noninvasive surrogate biomarkers

A tissue transcriptome driven classification of nephrotic syndrome patients identified a high risk group of patients with TNF activation and established a non-invasive marker panel for pathway activity assessment paving the way towards precision medicine trials in NS.\n\nAbstractNephrotic syndrome from primary glomerular diseases can lead to chronic kidney disease (CKD) and/or end-stage renal disease (ESRD). Conventional diagnoses using a combination of clinical presentation and descriptive biopsy information do not accurately predict risk for progression in patients with nephrotic syndrome, which complicates disease management. To address this challenge, a transcriptome-driven approach was used to classify patients with minimal change disease and focal segmental glomerulosclerosis in the Nephrotic Syndrome Study Network (NEPTUNE). Transcriptome-based classification revealed a group of patients at risk for disease progression. High risk patients had a transcriptome profile consistent with TNF activation. Non-invasive urine biomarkers TIMP1 and CCL2 (MCP1), which are causally downstream of TNF, accurately predicted TNF activation in the NEPTUNE cohort setting the stage for patient stratification approaches and precision medicine in kidney disease.

systems biology↗