Biology subjects

jiang, l.

Publications and source records attributed to jiang, l..

4 recordsLinked to original sources

bioRxiv2025

Single Cell Proteomics in the Developing Human Brain

Proteins are the functional effectors of virtually all biological processes, and accurately measuring their abundance and dynamics is essential for understanding development and disease. Although mRNA levels have historically been used as proxies for protein expression, growing evidence, especially from studies of the human cerebral cortex, has revealed widespread discordance between transcript and protein abundance. To directly address this limitation, we developed a rigorously optimized workflow that combines single-cell mass spectrometry with precise sample preparation to resolve, for the first time, quantitative proteomes of individual cells from the developing human brain. Our platform achieved deep proteomic coverage ([~]800 proteins per cell) even in immature prenatal human neurons (5-10 m diameter, [~]100 pg of protein per cell), capturing major brain cell types and enabling proteome-wide characterization at single-cell resolution. This approach revealed extensive transcriptome-proteome discordance across cell types, with particularly strong discrepancies in genes associated with neurodevelopmental disorders, a finding validated through orthogonal experiments. Proteins exhibited markedly higher cell-type specificity than their mRNA counterparts, underscoring the importance of proteomic-level analysis for resolving cellular identity and function. By reconstructing developmental trajectories from radial glia to excitatory neurons at the proteomic level, we identified dynamic stage-specific protein co-expression modules and pinpointed the intermediate progenitor-to-neuron transition as a molecularly vulnerable phase linked to autism. Altogether, by enabling single cell proteomics, this study establishes a foundational resource and technological advance for developmental neuroscience. It demonstrates that single-cell proteomics can capture critical developmental events and disease mechanisms that are undetectable at the transcript level. As this technology continues to improve in sensitivity and scalability, single-cell proteomics will become an indispensable tool for uncovering the molecular logic of brain development and for illuminating pathophysiological processes underlying neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

ZMS-6659, a selective Polθ helicase inhibitor, demonstrates anti-tumor activity as monotherapy and synergy effect with PARP inhibitors and topoisomerase inhibitors

The repair of DNA double strand break (DSB) is crucial for genome stability. Homologous recombination (HR) is a high-fidelity, error-free DSB repair pathway, and its dysfunction leads to genome instability and can result in tumorigenesis. In HR deficient contexts, microhomology-mediated end joining (MMEJ), dependent on DNA polymerase theta (Pol{theta}), is up-regulated to serve as a backup pathway for DSB repair. Several studies have proved that Pol{theta} inhibition causes synthetic lethality with HR deficiency, and Pol{theta} emerges as a potential DNA damage repair (DDR) target for the treatment of HR deficient tumors both as single agent or in combination with PARP inhibitors (PARPi). In addition, evidences show that the blockage of Pol{theta} can enhance the sensitivity to DNA damage agents. Herein, we characterized ZMS-6659, a highly potent small-molecule Pol{theta} inhibitor targeting the helicase domain. ZMS-6659 induces synthetic lethality in HR deficient models, elicits synergistic effects with even low dose of PARPi and delays PARPi resistance without additional hematotoxicity. Besides, ZMS-6659 also enhance the sensitivity to topoisomerase inhibitors in HR proficient cell lines. These findings support the clinical exploration of ZMS-6659 in combination with PARPi in HR deficient tumors, and suggest a potential application expansion beyond HR deficiency.

cancer biology↗

bioRxiv2024

Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease

To understand dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune and clinical markers of microbiomes from four body sites in 86 participants over six years. We found that microbiome stability and individuality are body-site-specific and heavily influenced by the host. The stool and oral microbiome were more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. Also, we identified individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlated across body sites, suggesting systemic coordination influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals showed altered microbial stability and associations between microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease. Study HighlightsO_LIThe stability of the human microbiome varies among individuals and body sites. C_LIO_LIHighly individualized microbial genera are more stable over time. C_LIO_LIAt each of the four body sites, systematic interactions between the environment, the host and bacteria can be detected. C_LIO_LIIndividuals with insulin resistance have lower microbiome stability, a more diversified skin microbiome, and significantly altered host-microbiome interactions. C_LI

microbiology↗

bioRxiv2018

Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein MDM2

The circadian clock relies on post-translational modifications to set the timing for degradation of core regulatory components and, thus, sets clock progression. Ubiquitin-modifying enzymes targeting clock components for degradation are known to mostly recognize phosphorylated substrates. A case in point is the circadian factor PERIOD 2 (PER2) whose phospho-specific turnover involves its recognition by {beta}-transducin repeat containing proteins ({beta}-TrCPs). Yet, the existence of this unique mode of regulation of PER2s stability falls short of explaining persistent oscillatory phenotypes reported in biological systems lacking functional elements of the phospho-dependent PER2 degradation machinery.\n\nIn this study, we challenge the phosphorylation-centric view that PER2 degradation enhances circadian rhythm robustness by i) identifying the PER2:MDM2 endogenous complex, ii) establishing PER2 as a previously uncharacterized substrate for MDM2, iii) revealing an alternative phosphorylation-independent mechanism for PER2 ubiquitin-mediated degradation, iv) pinpointing residues for ubiquitin modification, and v) establishing the importance of MDM2-mediated PER2 turnover for defining the circadian period length. Our results not only expand MDM2s suite of specific substrates beyond the cell cycle to include circadian components but also uncover novel regulatory players that likely impact our view of how other mechanisms crosstalk and modulate the clock itself.

molecular biology↗