Biology subjects

Lin, Y.-T.

Publications and source records attributed to Lin, Y.-T..

23 records · Page 2Linked to original sources

bioRxiv2020

Prediction of drug-protein interaction and drug repositioning using machine learning model

BackgroundTraditional drug development is time-consuming and expensive, while computer-aided drug repositioning can improve efficiency and productivity. In this study, we proposed a machine learning pipeline to predict the binding interaction between proteins and marketed or studied drugs. We then extended the predicted interactions to construct a protein network that could be applied to discover the potentially shared drugs between proteins and thus predict drug repositioning. MethodsBinding information between proteins and drugs from the Binding Database and the physicochemical properties of drugs from the ChEMBL database were used to build the machine learning models, i.e. support vector regression. We further measured proportionalities between proteins by the predicted binding affinity and introduced edge betweenness centrality to construct a protein similarity network for drug repositioning. ResultsAs the proof of concept, we demonstrated our machine learning approach is capable of reflecting the binding strength between drugs and the target protein. When comparing coefficients of protein models, we found proteins SYUA and TAU that may share common ligand which were not in our training data. Using the edge betweenness centrality network based on the prediction proportionality of protein models, we found a potential target, AK1C2, of aspirin and of which the binding interaction had been validated. ConclusionsOur study could not only be applied to drug repositioning by comparing protein models or searching the protein-protein network, but also to predict the binding strength once the sufficient experimental data was provided to train the protein models.

bioinformatics↗

bioRxiv2020

Robust and scalable manifold learning via landmark diffusion for long-term medical signal processing

Motivated by analyzing long-term physiological time series, we design a robust and scalable spectral embedding algorithm, coined the algorithm RObust and Scalable Embedding via LANdmark Diffusion (ROSE-LAND). The key is designing a diffusion process on the dataset, where the diffusion is forced to interchange on a small subset called the landmark set. In addition to demonstrating its application to spectral clustering and image segmentation, the algorithm is applied to study the long-term arterial blood pressure waveform dynamics during a liver transplant operation lasting for 12 hours long.

bioinformatics↗

bioRxiv2019

RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence

The molecular and genetic basis of tumor recurrence is complex and poorly understood. RIPK3 is a key effector in programmed necrotic cell death and, therefore, its expression is frequently suppressed in primary tumors. In a transcriptome profiling between primary and recurrent breast tumor cells from a murine model of breast cancer recurrence, we found that RIPK3, while absent in primary tumor cells, is dramatically re-expressed in recurrent breast tumor cells by an epigenetic mechanism. Unexpectedly, we found that RIPK3 knockdown in recurrent tumor cells reduced clonogenic growth, causing cytokinesis failure, p53 stabilization, and repressed the activities of YAP/TAZ. These data uncover a surprising role of the pro-necroptotic RIPK3 kinase in enabling productive cell cycle during tumor recurrence. Remarkably, high RIPK3 expression also rendered recurrent tumor cells exquisitely dependent on extracellular cystine and undergo programmed necrosis upon cystine deprivation. The induction of RIPK3 in recurrent tumors unravels an unexpected mechanism that paradoxically confers on tumors both growth advantage and necrotic vulnerability, providing potential strategies to eradicate recurrent tumors.

cancer biology↗

bioRxiv2018

CBX2 is required during male sex determination to repress female fate at bivalent loci

The epigenetic mechanisms that regulate the male vs. female cell-fate decision in the mammalian bipotential gonad are poorly understood. In this study, we developed a quantitative genome-wide profile of H3K4me3 and H3K27me3 in isolated XY and XX gonadal supporting cells before and after sex determination. We show that male and female sex-determining (SD) genes are bivalent before sex determination, providing insight into how the bipotential state of the gonad is established at the epigenetic level. After sex determination, many SD genes of the alternate pathway remain bivalent, possibly contributing to the ability of these cells to transdifferentiate even in adults. It was previously shown that loss of CBX2, the Polycomb group subunit that binds H3K27me3 and mediates silencing, leads to loss of Sry and male-to-female sex reversal. The finding that many genes in the Wnt signaling pathway were targeted for H3K27me3-mediated repression in Sertoli cells led us to test whether deletion of Wnt4 could rescue male development in Cbx2 mutants. We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice. Furthermore, we show that CBX2 directly binds the downstream Wnt signaler Lef1, a female-promoting gene that remains bivalent in Sertoli cells. Our results suggest that stabilization of the male fate requires CBX2-mediated repression of bivalent female-determining genes, which would otherwise block Sry expression and male development.\n\nAuthor SummaryDuring development, the bipotential fetal gonad can commit to the male fate and develop as a testis, or to the female fate and develop as an ovary. Mutation of the epigenetic regulator CBX2 leads to ovary development in XY embryos, suggesting a critical role for chromatin remodeling during sex determination. However, the epigenetic mechanisms that regulate the male vs. female cell-fate decision in the mammalian bipotential gonad are poorly understood. In this study, we developed a genome-wide profile of two histone modifications that play critical roles during development: H3K27me3 (repressive) and H3K4me3 (active). We find that sex-determining genes that are initially co-expressed in XX and XY bipotential gonads are bivalent (marked by both H3K4me3 and H3K27me3) prior to sex determination, poised to engage either the male or female fate. Remarkably, after sex determination, repressed genes that promote the alternate fate remain bivalent. We show that stabilization of the male fate requires CBX2-mediated repression of bivalent female-determining genes, which would otherwise block testis development. Our study provides insight into how the bipotential state of the gonad is established at the epigenetic level, and how the male fate is stabilized by repression of the female fate during sex determination.

developmental biology↗

bioRxiv2018

Emergence of mosaic plasmids harboring Tn1546-ermB element in Staphylococcus aureus isolates

Antimicrobial resistance in Staphylococcus aureus is a major problem and the acquisition of resistance genes may occur by horizontal gene transfer (HGT). The transposon, an important means of HGT, is recognized as a mobile genetic element that can integrate in plasmids, replicate and transfer to other strains. We have previously reported a novel structure of the Enterococcus faecium-originated Tn1546-ermB element in S. aureus. The emergence of the Tn1546-like element is an emerging problem that requires continuous monitoring. In the present study, we expand the examination of Tn1546-ermB element to ermB-positive methicillin-susceptible S. aureus (MSSA) (n = 116) and ermB-positive methicillin-resistant S. aureus (MRSA) (n = 253) during a 16-year period, from 2000 to 2015. PCR mapping showed that 10 MSSA and 10 MRSA carried the Tn1546-ermB element. The 10 MSSA belonged to three sequence types (ST), ST7 (n = 6), ST5 (n = 3), and ST59 (n = 1), and the 10 MRSA belonged to two STs, ST188 (n = 8) and ST965 (n = 2). Since only clonal complex 5 (including ST5, ST85, ST231, and ST371) MRSA, ST8 MRSA and ST5 MSSA have been previously reported to carry Tn1546 plasmids, this is the first report describing the presence of the Tn1546-ermB element in ST7/5/59 MSSA and ST188/965 MRSA. Plasmid sequencing revealed that the Tn1546-ermB element was harbored by five different mosaic plasmids. In addition to resistance genes, some plasmids also harbored toxin genes.

microbiology↗