Biology subjects

Cen, S.

Publications and source records attributed to Cen, S..

5 recordsLinked to original sources

bioRxiv2026

Scalable phylodynamic inference of mutational and epistatic fitness effects with multi-feature birth-death models

Fitness is a complex phenotype determined by many different genomic features, their interactions with each other and the environment. For rapidly evolving microbes like viruses and bacteria, phylodynamic multi-feature birth-death (MFBD) models provide a way to infer the fitness of lineages with different genotypes from reconstructed phylogenies. However, existing phylodynamic methods assume very simple additive or multiplicative genotype-to-fitness (G-to-F) mappings that typically ignore epistatic interactions among features. We developed a gradient-based Bayesian MFBD framework for estimating the fitness effects of multiple features while allowing for both additive and epistatic G-to-F maps. The framework uses Hamiltonian Monte Carlo for posterior inference and incorporates shrinkage priors to regularize weakly supported fitness effects without cross-validation. In simulations, Bayesian inference performs well at recovering additive fitness effects, with accuracy and precision improving consistently with increasing tree size. While epistatic effects are more difficult to estimate because they depend on the co-occurrence of mutations, shrinkage improves estimation when interaction effects are weak or sparsely supported. Simulations with misspecified additive models show that ignoring moderate or strong epistasis can bias estimates of individual mutational effects. We applied the framework to a time-calibrated \textit{Escherichia coli} ST131 phylogeny with 1763 samples and estimated fitness effects for several mutations in the quinolone resistance-determining region (QRDR). These results show that Bayesian phylodynamic inference can be used to learn the genomic determinants of fitness while quantifying uncertainty in mutational and epistatic fitness effects.

evolutionary biology↗

bioRxiv2025

Segmented poly(A) tails with microRNA target sites confer tissue-specific regulation for mRNA therapeutics

Targeted delivery and controlled expression of mRNA-LNPs are critical for the development of safe and effective mRNA medicines. However, efficient post-delivery regulation of mRNA-LNP expression remains challenging. In this study, we engineered segmented poly(A) tail variants that function as gene-specific regulatory elements for synthetic mRNAs. Specifically, we inserted microRNA target sites (MTS) for miR-122 or miR-142 at various positions of the poly(A) tail of synthesized luciferase reporter mRNA. These modifications significantly reduced luciferase expression in non-target tissues in vitro and in vivo, demonstrating position-dependent selective expression control. Furthermore, by incorporating triple-MTS sequences for miR-142, miR-126, and miR-148a in all possible combinations at the 5 end of the poly(A) tail, we identified triple-MTS arrangements that simultaneously decrease luciferase activities in three non-target hepatic cell types, while preserving robust expression in hepatocytes. The results highlighted the importance of MTS insertion order for optimal mRNA silencing. These triple-MTS modules significantly expanded the utility of single miRNA-responsive elements, enabling cell-type selective regulation for mRNA therapeutics. By complementing tissue-tropic delivery LNPs, our mRNA cargo regulatory elements have the potential to improve tissue and cell type selectivity as a novel platform for post-delivery regulation of mRNA-LNP.

bioengineering↗

bioRxiv2024

Age-Related Decline in BBB Function is More Pronounced in Males than Females

The blood-brain barrier (BBB) plays a pivotal role in protecting the central nervous system (CNS), shielding it from potential harmful entities. A natural decline of BBB function with aging has been reported in both animal and human studies, which may contribute to cognitive decline and neurodegenerative disorders. Limited data also suggest that being female may be associated with protective effects on BBB function. Here we investigated age and sex-dependent trajectories of perfusion and BBB water exchange rate (kw) across the lifespan in 186 cognitively normal participants spanning the ages of 8 to 92 years old, using a non-invasive diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI technique. We found that the pattern of BBB kw decline with aging varies across brain regions. Moreover, results from our DP-pCASL technique revealed a remarkable decline in BBB kw beginning in the early 60s, which was more pronounced in males. In addition, we observed sex differences in parietal and temporal regions. Our findings provide in vivo results demonstrating sex differences in the decline of BBB function with aging, which may serve as a foundation for future investigations into perfusion and BBB function in neurodegenerative and other brain disorders. Significance statementThe blood-brain barrier (BBB) serves as a critical protection mechanism for the CNS. A natural decline of BBB function with aging has been reported in both animal and human studies, with possible differences in BBB function by sex. Using our MRI technique, DP-pCASL that measures water exchange rate (kw) without contrast in 186 participants from diverse race and age groups, we identified age and sex-specific patterns in BBB kw especially in parietal and temporal regions. We observed of a decline in kw beginning in the early 60s, especially in males. Our study unveils the dynamic spatiotemporal pattern of kw differences with age and sex, which serve as a foundation for understanding aberrations of BBB function in neurodegenerative and other brain disorders.

neuroscience↗

bioRxiv2023

Exploring the accuracy and limits of algorithms for localizing recombination breakpoints

Phylogenetic methods are widely used to reconstruct the evolutionary relationships among species and individuals. However, recombination can obscure ancestral relationships as individuals may inherit different regions of their genome from different ancestors. It is therefore often necessary to detect recombination events, locate recombination breakpoints and select recombination-free alignments prior to reconstructing phylogenetic trees. While many earlier studies examined the power of different methods to detect recombination, very few have examined the ability of these methods to accurately locate recombination breakpoints. In this study, we simulated genome sequences based on ancestral recombination graphs and explored the accuracy of three popular recombination detection methods: MaxChi, 3SEQ and GARD. The accuracy of inferred breakpoint locations was evaluated along with the key factors contributing to variation in accuracy across data sets. While many different genomic features contribute to the variation in performance across methods, the number of informative sites consistent with the pattern of inheritance between parent and recombinant child sequences always has the greatest contribution to accuracy. While partitioning sequence alignments based on identified recombination breakpoints can greatly decrease phylogenetic error, the quality of phylogenetic reconstructions depends very little on how breakpoints are chosen to partition the alignment. Our work sheds light on how different features of recombinant genomes affect the performance of recombination detection methods and suggests best practices for reconstructing phylogenies based on recombination-free alignments.

bioinformatics↗

bioRxiv2018

HIV-1 antisense protein of different clades induces autophagy and associates to the autophagy factor p62

Over recent years, strong support argues for the existence of an HIV-1 protein encoded by antisense transcripts and termed Antisense Protein (ASP). Furthermore, a recent in silico analysis has provided evidence for its recent appearance in the genome of HIV-1. We have previously detected ASP in various mammalian cell lines by Western blot (WB), flow cytometry and confocal microscopy analyses and reported that it induced autophagy, potentially through multimer formation. The aim of the current study was to examine autophagy induction by testing ASP from different clades, and to identify the implicated autophagy factors. We firstly confirmed that NL4.3-derived ASP was interacting with itself and that multimer formation was dependent on its amino region. Removal of this region was associated with reduced level of induced autophagy, as assessed by autophagosome formation but deletion of the most amino cysteine triplet did not totally abrogate multimer and autophagosome formation. Expression vectors of ASP from different clades were next tested and led to detection of monomers and varying levels of multimers with concomitant induced autophagy, as determined by increased LC3-II and decreased p62 (SQSTM1) levels. Through confocal microscopy, ASP was noted to co-localize with p62 and LC3-II in autophagosome-like cellular structures. CRISPR-based knock-out of ATG5, ATG7 and p62 genes led to increased stability in the levels of ASP. Furthermore, co-immunoprecipitation experiments demonstrated the interaction between p62 and ASP, which was dependent on the PB1 domain of p62. Interestingly, immunoprecipitation experiments further supported that ASP is ubiquitinated and that ubiquitination was also responsible for the modulation of its stability. We are thus suggesting that ASP induces autophagy through p62 interaction and that its abundance is controlled by autophagy- and Ubiquitin/Proteasome System (UPS)-mediated degradation in which ubiquitin is playing an important role. Understanding the mechanisms underlying the degradation of ASP is essential to better assess its function.\n\nAuthor SummaryIn the present study, we provide the first evidence that a new HIV-1 protein termed ASP when derived from different clades act similarly in inducing autophagy, an important cellular process implicated in the degradation of excess or defective material. We have gained further knowledge on the mechanism mediate the activation of autophagy and have identified an important interacting partner. Our studies have important ramification in the understanding of viral replication and the pathogenesis associated with HIV-1 in infected individuals. Indeed, autophagy is implicated in antigen presentation during immune response and could thus be rendered inefficient in infected cells, such as dendritic cells. Furthermore, a possible link with HIV-1-associated Neurological Disorder (HAND) might also be a possible association with the capacity of ASP to induce autophagy. Our studies are thus important and demonstrate the importance in conducting further studies on this protein, as it could represent a new interesting target for antiretroviral therapies and vaccine design.

microbiology↗