Biology subjects

Lin, W.-J.

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

12 recordsLinked to original sources

bioRxiv2026

Parental care enhances reproductive success without remodeling the carcass microbiome in a wild burying beetle

Nutrient cycling depends on interactions between insect decomposers and the microbial communities that colonize ephemeral resources such as animal carcasses. Burying beetles (Nicrophorus spp.) are thought to manipulate carcass microbiomes to facilitate reproduction, yet most experimental work relies on a few standardized laboratory carcasses that obscure the ecological heterogeneity beetles face in the wild. Using 76 carcasses from 27 vertebrate species of birds, mammals, and reptiles, we manipulated Nicrophorus nepalensis parental care and characterized carcass, adult-gut, and larval-gut microbiomes by 16S rRNA sequencing. Parental care strongly increased breeding success and brood mass, and buffered reproductive success against variation in carcass identity. By contrast, carcass type and decomposition stage, not care, primarily structured the carcass microbiome; a modest care signature emerged only late in decomposition, was strongest in the adult gut, and was absent from the larval gut. Parental care thus acts principally as a direct driver of reproductive success rather than by remodeling the carcass or larval microbiomes.

ecology↗

bioRxiv2025

Generalization but not strengthening of negative memories drives the development of depression-like behaviors

Individuals with depression exhibit intensified and generalized negative memories. However, how prior memories actually influence onset and/or progression of depression, particularly whether the strengthening or the generalization of prior memories play a key role, is poorly understood. Here, we introduced behavioral paradigms to differentiate between memory strengthening and generalization, and found that negative experiences that produced memory overgeneralization, but not strengthening, induced depression-like behaviors. Furthermore, we identified that the medial prefrontal cortex (mPFC) to the bed nucleus of the stria terminals (BNST) projection functionally linked memory generalization to depression, together with single-cell calcium imaging which revealed a significant overlap in the mPFCBNST neuronal ensemble encoding depression-like behaviors with that encoding generalized memory, but not memory strength. Circuit-based transcriptomic analysis and chromophore-assisted light inactivation demonstrated that triggering actin remodeling in the mPFCBNST neurons, a memory consolidation mechanism enhanced generalization while reducing memory strength, also induced depression-like behaviors. Collectively, these findings suggest generalization of negative memories as a primary factor that drives depression-like behaviors, highlighting the importance of early identification of individuals at risk for depression who exhibit overgeneralized negative memories, and targeting overgeneralized negative memories in the treatment of depression.

animal behavior and cognition↗

bioRxiv2024

Structure of human MUTYH and functional profiling of cancer-associated variants reveal an allosteric network between its cluster cofactor and active site required for DNA repair

MUTYH is a clinically important DNA glycosylase that thwarts mutations by initiating base-excision repair at 8-oxoguanine (OG):A lesions. The roles for its [4Fe-4S] cofactor in DNA repair remain enigmatic. Functional profiling of cancer-associated variants near the [4Fe-4S] cofactor revealed that most variations abrogate both retention of the cofactor and enzyme activity. Surprisingly, R241Q and N238S retained the metal center and bound substrate DNA tightly but were completely inactive. We solved the crystal structure of human MUTYH bound to a transition state mimic and this revealed that Arg241 and Asn238 build an H-bond network connecting the [4Fe-4S] cluster to the catalytic Asp236 that mediates base excision. The structure of the bacterial MutY variant R149Q, along with molecular dynamics simulations of the human enzyme, show the cofactor functions to position and activate the catalytic Asp. These results suggest that allosteric cross-talk between the DNA binding [4Fe-4S] cofactor and the base excision site regulate DNA repair.

biochemistry↗

bioRxiv2024

iLipidome: enhancing statistical power and interpretability using hidden biosynthetic interdependencies in the lipidome

Numerous biological processes and diseases are influenced by lipid composition. Advances in lipidomics are elucidating their roles, but analyzing and interpreting lipidomics data at the systems level remain challenging. To address this, we present iLipidome, a method for analyzing lipidomics data in the context of the lipid biosynthetic network, thus accounting for the interdependence of measured lipids. iLipidome enhances statistical power, enables reliable clustering and lipid enrichment analysis, and links lipidomic changes to their genetic origins. We applied iLipidome to investigate mechanisms driving changes in cellular lipidomes following supplementation of docosahexaenoic acid (DHA) and successfully identified the genetic causes of alterations. We further demonstrated how iLipidome can disclose enzyme-substrate specificity and pinpoint prospective glioblastoma therapeutic targets. Finally, iLipidome enabled us to explore underlying mechanisms of cardiovascular disease and could guide the discovery of early lipid biomarkers. Thus, iLipidome can assist researchers studying the essence of lipidomic data and advance the field of lipid biology.

systems biology↗

bioRxiv2024

Functional and multi-omic aging rejuvenation with GLP-1R agonism

Identifying readily implementable methods that can effectively counteract aging is urgently needed for tackling age-related degenerative disorders. Here, we conducted functional assessments and deep molecular phenotyping in the aging mouse to demonstrate that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment attenuates body-wide age-related changes. Apart from improvements in physical and cognitive performance, the age-counteracting effects are prominently evident at multiple omic levels. These span the transcriptomes and DNA methylomes of various tissues, organs and circulating white blood cells, as well as the plasma metabolome. Importantly, the beneficial effects are specific to aged mice, not young adults, and are achieved with a low dosage of GLP-1RA which has a negligible impact on food consumption and body weight. The molecular rejuvenation effects exhibit organ-specific characteristics, which are generally heavily dependent on hypothalamic GLP-1R. We benchmarked the GLP-1RA age-counteracting effects against those of mTOR inhibition, a well-established anti-aging intervention, observing a strong resemblance across the two strategies. Our findings have broad implications for understanding the mechanistic basis of the clinically observed pleiotropic effects of GLP-1RAs, the design of intervention trials for age-related diseases, and the development of anti-aging-based therapeutics.

systems biology↗

bioRxiv2023

LipidSIM: inferring mechanistic lipid biosynthesis perturbations from lipidomics with a flexible, low-parameter, systematic Markov Modeling framework

Lipid metabolism is a complex and dynamic system involving numerous enzymes at the junction of multiple metabolic pathways. Disruption of these pathways leads to systematic dyslipidemia, a hallmark of many pathological developments, such as nonalcoholic steatohepatitis and diabetes. Recent advances in computational tools can provide insights into the dysregulation of lipid biosynthesis, but limitations remain due to the complexity of lipidomic data, limited knowledge of interactions among involved enzymes, and technical challenges in standardizing across different lipid types. In this study, we present a low-parameter, biologically interpretable framework named Lipid Synthesis Investigative Markov model (LipidSIM), which models and predicts the source of perturbations in lipid biosynthesis from lipidomic data. LipidSIM achieves this by accounting for the interdependency between the lipid species via the lipid biosynthesis network and generates testable hypotheses regarding changes in lipid biosynthetic reactions. This feature allows the integration of lipidomics with other omics types, such as transcriptomics, to elucidate the direct driving mechanisms of altered lipidomes due to treatments or disease progression. To demonstrate the value of LipidSIM, we first applied it to hepatic lipidomics following Keap1 knockdown and found changes in mRNA expression of the lipid pathways were consistent with the LipidSIM-predicted fluxes. Second, we used it to study lipidomic changes following intraperitoneal injection of CCl4 to induce fast NAFLD/NASH development and the progression of fibrosis and hepatic cancer. Finally, to show the power of LipidSIM for classifying samples with dyslipidemia, we used a Dgat2-knockdown study dataset. Thus, we show that as it demands no a priori knowledge of enzyme kinetics, LipidSIM is a valuable and intuitive framework for extracting biological insights from complex lipidomic data.

bioinformatics↗

bioRxiv2023

Transitions in density, pressure, and effective temperature drive collective cell migration into confining environments

Epithelial cell collectives migrate through tissue interfaces and crevices to orchestrate processes of development, tumor invasion, and wound healing. Naturally, traversal of cell collective through confining environments involves crowding due to the narrowing space, which seems tenuous given the conventional inverse relationship between cell density and migration. However, physical transitions required to overcome such epithelial densification for migration across confinements remain unclear. Here, in contiguous microchannels, we show that epithelial (MCF10A) monolayers accumulate higher cell density before entering narrower channels; however, overexpression of breast cancer oncogene +ErbB2 reduced this need for density accumulation across confinement. While wildtype MCF10A cells migrated faster in narrow channels, this confinement sensitivity reduced after +ErbB2 mutation or with constitutively-active RhoA. The migrating collective developed pressure differentials upon encountering microchannels, like fluid flow into narrowing spaces, and this pressure dropped with their continued migration. These transitions of pressure and density altered cell shapes and increased effective temperature, estimated by treating cells as granular thermodynamic system. While +RhoA cells and those in confined regions were effectively warmer, cancer-like +ErbB2 cells remained cooler. Epithelial reinforcement by metformin treatment increased density and temperature differentials across confinement, indicating that higher cell cohesion could reduce unjamming. Our results provide experimental evidence for previously proposed theories of inverse relationship between density and motility-related effective temperature. Indeed, we show across cell lines that confinement increases pressure and effective temperature, which enable migration by reducing density. This physical interpretation of collective cell migration as granular matter could advance our understanding of complex living systems.

biophysics↗

bioRxiv2023

Targeted and selective knockout of the TLQP-21 neuropeptide unmasks its unique role in energy homeostasis

Pro-peptide precursors are processed into biologically active peptide hormones or neurotransmitters, each playing an essential role in physiology and disease. Genetic loss of function of a pro-peptide precursor results in the simultaneous ablation of all biologically-active peptides within that precursor, often leading to a composite phenotype that can be difficult to align with the loss of specific peptide components. Due to this biological constraint and technical limitations, mice carrying the selective ablation of individual peptides encoded by pro-peptide precursor genes, while leaving the other peptides unaffected, have remained largely unaddressed. Here, we developed and characterized a mouse model carrying the selective knockout of the TLQP-21 neuropeptide ({Delta}TLQP-21) encoded by the Vgf gene. To achieve this goal, we used a knowledge-based approach by mutating a codon in the Vgf sequence leading to the substitution of the C-terminal Arginine of TLQP-21, which is the pharmacophore as well as an essential cleavage site from its precursor, into Alanine (R21[->]A). We provide several independent validations of this mouse, including a novel in-gel digestion targeted mass spectrometry identification of the unnatural mutant sequence, exclusive to the mutant mouse. {Delta}TLQP-21 mice do not manifest gross behavioral and metabolic abnormalities and reproduce well, yet they have a unique metabolic phenotype characterized by a temperature-dependent resistance to diet-induced obesity and activation of the brown adipose tissue.

physiology↗

bioRxiv2022

Increased academic performance and prolonged career duration among Taiwanese academic faculty in ecology and evolutionary biology

Academic job markets have become increasingly challenging worldwide, yet it remains poorly characterized how competitively-successful candidates should be and what the underlying determinants of their success are. Focusing on the field of ecology and evolutionary biology, we analyzed the academic performance (measured as h-index) as well as the duration before recruitment as a new faculty member and promotion to full professor of 145 principal investigators (PI) over the past 34 years in Taiwan. We found that PIs had higher performance and longer duration before recruitment more recently. Performance before promotion remained stable, whereas the duration increased over time. The origin and prestige of doctorate had no effect on the performance or duration either before recruitment or before promotion. We also found that the difference in performance before and after recruitment ("After" performance -- "Before" performance) decreased in recent years, with PIs recruited in earlier years maintaining their performance after recruitment while those recruited in later years exhibiting a performance drop. While PIs performed equally well before and after recruitment irrespective of doctorate origin, those with domestic PhD degrees showed a decrease in performance after promotion compared to their counterparts with foreign degrees. Taken together, our findings reveal a prolonged career duration for researchers as a result of intensifying competition in academia, and highlight the increasingly crucial role of academic performance, rather than PhD degree itself, in determining academic success.

scientific communication and education↗

bioRxiv2019

Influence of age and gender on taste function of healthy subjects

ObjectivesTo determine the influences of age and gender on the taste functions of healthy Taiwanese. MethodsWe evaluated taste functions of healthy Taiwanese using the whole mouth suprathreshold taste test, along with the taste quad test. In the whole-mouth test, we applied in a counterbalanced order sweet, sour, salty, and bitter solutions, each at 5 different suprathreshold concentrations to subjects, who were instructed to sip and swish in mouth twice. Each subject had to indicate the taste quality, and to rate the intensity and unpleasantness/pleasantness of each taste of the solutions. In the quad test, the 4 quadrants of the tongue surface were tested by dripping one concentration of sweet, sour, salty, or bitter solutions for 6 times. Subjects then indicated the taste quality, and rated the intensity of the solution. ResultsSubjects were divided into groups based on their gender and age: 20-39 years, 40-59 years, or [≥] 60 years. We found that in the whole mouth taste test, the total correct identification score dropped with age. But identifying sweet and salty qualities was not affected by age. No differences were found between male and female, except women scored better than men for sweet quality in the age group of 40-59 years. The total correct identification score of the taste quad test also decreased with an increased age of the taste quad test, without gender differences. ConclusionBoth age and gender affected the taste functions in healthy Taiwanese to some extent, and differences were dependent on age, tongue region, and taste quality.

physiology↗

bioRxiv2019

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

With advances in single-cell genomics, molecular signatures of cells comprising the brain vasculature are revealed in unprecedented detail1,2, yet the ageing-associated cell subtype transcriptomic changes which may contribute to neurovascular dysfunction in neurodegenerative diseases3-7 remain elusive. Here, we performed single-cell transcriptomic profiling of brain endothelial cells (EC) in young adult and aged mice to characterize their ageing-associated genome-wide expression changes. We identified zonation-dependent transcriptomic changes in aged brain EC subtypes, with capillary ECs exhibiting the most transcriptomic alterations. Pathway enrichment analysis revealed altered immune/cytokine signaling in ECs of all vascular segments, while functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism were most prominently implicated in ECs of the capillary bed - the primary site where ECs and other neurovascular unit (NVU) cell types closely interact and coordinate to regulate BBB and cerebral blood flow in health and diseased conditions8-17. Furthermore, an overrepresentation of Alzheimers disease (AD)-associated genes identified from GWAS studies was evident among the human orthologs of differentially expressed genes of aged capillary ECs but not other EC subtypes. Importantly, for numerous EC-enriched differentially expressed genes with important functional roles at the BBB and/or association with AD, we found concordant expression changes in human aged or AD brains. Finally, we demonstrated that treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, strongly reverses transcriptomic changes in ECs and largely reduces BBB leakage in the aged brain. Thus, our study provides insights into detailed transcriptomic alterations underlying brain EC ageing that are complex with subtype specificity yet amenable to pharmacological interventions.

neuroscience↗

bioRxiv2018

Multiscale causal network models of Alzheimer’s disease identify VGF as a key regulator of disease

Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimers disease (AD) remains elusive. To elucidate its complex nature, we constructed multiscale causal network models on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene and protein expression into probabilistic causal models that enabled detection and prioritization of high-confidence key drivers of AD, including the top predicted key driver VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was achieved, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF versus controls. Our findings support a causal and/or protective role for VGF in AD pathogenesis and progression.\n\nOne sentence summaryVGF protects against Alzheimers disease

genomics↗