Biology subjects

Lau, P.

Publications and source records attributed to Lau, P..

15 recordsLinked to original sources

bioRxiv2026

Morphological evolution and phylogeny are unlinked in Hawaiian Doryopteris (Cheilanthoideae: Pteridaceae)

Premise of the study: Doryopteris J.Sm. is a genus of dry-adapted ferns found widely across the southern hemisphere and the tropics. In the Hawaiian Islands, the genus is represented by four endemic species and one putative hybrid. Two of the endemic species (D. decora and D. decipiens) are widespread across all major islands, while two (D. angelica and D. takeuchii) are federally and state-listed endangered single-island endemics.We aimed to resolve the evolutionary relationships and biogeographic history of Hawaiian Doryopteris. Methods: We used a target-capture approach and the GoFlag 408 flagellate land plant probe set to sequence more than 400 nuclear loci for 40 Hawaiian and 29 non-Hawaiian individuals in Doryopteris and the related genera Lytoneuron and Ormopteris. After processing the sequences into alignments and single nucleotide polymorphism sites, we performed phylogenetic inference and population-level principal component analyses. Key results: We infer that Hawaiian Doryopteris are monophyletic and are nested within the pantropical species D. concolor. Within Hawai'i, clades and clusters of individuals correspond to geographical, geological, and climatological factors, more so than species identifications, with a few exceptions. We posit that Hawaiian Doryopteris represents an incipient radiation at the very earliest stages of divergence, and that budding speciation has led to non-monophyly of several taxa. Conclusions Our inference using genome-wide sequencing data sheds light on the complex evolutionary history of Hawaiian Doryopteris. Overall, the phylogeny of Hawaiian Doryopteris shows strong links with geographical, geological, and climatological processes and little with morphological evolution.

evolutionary biology↗

bioRxiv2026

Exon Resolved Dissection of Shared, Unique, and Antagonistic Functions of ZFAS1 Isoforms

The long noncoding RNA ZFAS1 plays a role in cell proliferation and has been linked to cancer development and prognosis. However, the ZFAS1 locus is predicted to encode over 40 ZFAS1 splice variants, which remain largely uncharacterized. To shed light on the role of ZFAS1 in hepatocyte models, we examined the transcriptome-wide effects of separately targeting three exons present in representative ZFAS1 variants with gapmer antisense oligonucleotides. Evidence of cross-exon compensatory regulation was obtained by qRT-PCR. Although targeting resulted in a subset of concerted transcript perturbations-indicating specificity and shared functionalities-the overall effects were predominantly non-redundant. Overrepresentation analyses revealed that proximal exon and distal exon targeting affected cell cycle and transcription regulation, respectively. Strikingly, interrogation of the entire transcriptome with gene set enrichment analysis identified a shared subset of pathways related to cell-cycle control and translation, which were affected antagonistically in an exon-dependent manner. Whereas targeting the proximal exon was predicted to broadly compromise cell-cycle and translational functions, targeting distal exons produced contrasting effects on these processes. Together, these findings demonstrate that the arrangement of ZFAS1 exons can markedly modulate its function.

cell biology↗

bioRxiv2025

Seasonal frost improves probiotic and nutrient availability in fermented vegetables

Climate change is shifting seasonal patterns in temperate regions, increasing the likelihood of early frost and raising questions about its impact on food production and quality. In this study, we tested how a single seasonal frost event influences microbial communities, fermentation dynamics, and the nutritional profile of naturally fermented cabbage and carrots, two cold-tolerant crops commonly grown in the Northeast US Using microbial sequencing, metagenomic analysis, and targeted vitamin assays, we found that frost exposure had no negative impact on microbial diversity or fermentation outcomes. Instead, it was associated with subtle shifts in microbial composition and increased abundance of genes involved in vitamin biosynthesis, including those linked to vitamin K{square}, B{square}{square}, and threonine. These genetic changes corresponded to higher concentrations of vitamins A and E in fermented carrots and vitamin K{square} in fermented cabbage. Our findings suggest that frost can enhance the nutritional and sensory qualities of fermented vegetables, offering a model for a new climate-resilient strategy for producing value-added, regionally distinctive food products.

microbiology↗

bioRxiv2025

The SAFE Labs Handbook: community-driven commitments for group leaders to improve lab culture

Creating positive and equitable lab environments has become a growing priority for the scientific community and funders of scientific research. Research institutions typically respond to this need by providing mandatory or optional training opportunities for their staff. However, there is no established resource for group leaders to improve their lab culture with concrete action points for implementation. Here, we introduce the SAFE Labs Handbook: a collection of thirty "commitments" which can be verifiably actioned without requiring institutional support. These commitments were collaboratively developed by thirteen group leaders in life sciences, from institutions across eight countries, instigated through the 2024 SAFE Labs workshop. The importance of each commitment has been scored by more than 200 researchers, at various career stages, from more than twenty countries. Even though all commitments were rated as significantly important by scientists from all career stages, implementation rates were notably low (< 25%). Lab members reported higher importance scores than group leaders, with large divergences indicating where group leaders may underestimate the potential impact on lab culture. Indeed, the overall implementation rate was correlated with importance score for group leaders, but not lab members. Strikingly, more than 95% of group leaders said they would consider implementing the handbook commitments. Given the high importance-scores and low-implementation rates, the SAFE Labs Handbook represents a unique, community-driven tool with significant potential to improve lab culture on a global scale.

scientific communication and education↗

bioRxiv2025

Deciphering the role of the lncRNA TRIBAL in hepatocyte models

We recently reported that the long non-coding RNA TRIBAL/TRIB1AL was required to sustain key hepatocyte functions. Here, we identify HepaRG cells as a model for studying TRIBAL and provide additional validation and functional insights. In contrast to HepG2 and HuH-7 cells, differentiated HepaRG cells showed similarities to primary hepatocytes in response to TRIBAL suppression. TRIBAL suppression was associated with reduced HNF4A and MLXIPL abundance in hepatocytes and HepaRG cells. TRIBAL targeting using a panel of targeting ASOs confirmed specificity. Comparing TRIBAL-suppressed hepatocyte and HepaRG transcriptomics identified extensive functional overlap. Biological ontologies associated with key hepatic metabolic functions were predicted to be inhibited in both models. Comparative analyses with TRIB1-suppressed HepaRG cells, a major metabolic regulator vicinal to TRIBAL, also revealed extensive functional congruence with TRIBAL. Interestingly, TRIBAL transduction failed to restore function in TRIBAL-suppressed cells, which may be linked to structural differences, as supported by contrasting RNAseR sensitivities between the endogenous and transduced forms. In summary, these findings support the use of HepaRG cells as an experimental model to study TRIBAL and underscore its importance in regulating key hepatocyte genes essential for metabolic function.

cell biology↗

bioRxiv2024

Epigenetic and 3D genome reprogramming during the aging of human hippocampus

Age-related cognitive decline is associated with altered physiology of the hippocampus. While changes in gene expression have been observed in aging brain, the regulatory mechanisms underlying these changes remain underexplored. We generated single-nucleus gene expression, chromatin accessibility, DNA methylation, and 3D genome data from 40 human hippocampal tissues spanning adult lifespan. We observed a striking loss of astrocytes, OPC, and endothelial cells during aging, including astrocytes that play a role in regulating synapses. Microglia undergo a dramatic switch from a homeostatic state to a primed inflammatory state through DNA methylome and 3D genome reprogramming. Aged cells experience erosion of their 3D genome architecture. Our study identifies age-associated changes in cell types/states and gene regulatory features that provide insight into cognitive decline during human aging.

genomics↗

bioRxiv2024

Constitutive Photomorphogenesis Protein 1 homolog (COP1) sustains nuclear factor-4 alpha function in human hepatocyte models

Constitutive Photomorphogenesis Protein 1 homolog (COP1) is a conserved E3 ligase with key roles in several biological systems. Prior work in hepatocyte derived tumors categorized COP1 as an oncogene but its role in untransformed hepatocytes remains largely unexplored. Here we have investigated the role of COP1 in primary human hepatocytes as well as in two transformed hepatocyte models, HepG2 and HuH-7 cells. Contrary to a previous report, COP1 suppression via siRNA had no noticeable impact on HepG2 and HuH-7 proliferation and was associated with contrasting rather than congruent transcriptome changes. Clustering analyses identified patterns indicative of perturbed metabolism in primary hepatocytes and HepG2 cells whereas patterns pointed to cell proliferation impacts in HuH-7 cells. In HepG2 and primary hepatocytes, COP1 suppression reduced the expression important hepatic regulators and markers, which could be restored by the introduction of a siRNA resistant COP1 transgene. COP1 downregulation reduced hepatic nuclear factor-4 alpha (HNF4A) abundance and function, as assessed by lower abundance of key HNF4A targets and reduced APOB secretion. HNF4A restoration partially rescued COP1 silencing in HepG2 cells. This study identifies COP1 as a key regulator of hepatocyte function, in part via HNF4A. COP1 was required to maintain HNF4A abundance and function in primary hepatocytes and in HepG2 cells, but not in HuH-7 cells. Lastly, by demonstrating contrasting roles of COP1 in HuH-7 and HepG2 cells, our findings also challenge previous work linking COP1 to hepatic tumorigenesis.

cancer biology↗

bioRxiv2023

Internal Ribosome Entry Sites act as Effector Domain in linear and circular antisense long non-coding SINEUP RNAs

SINEUPs are antisense long non-coding RNAs that enhance translation of overlapping sense mRNAs through the activity of two domains: a SINEB2 sequence UP-regulating translation (Effector Domain, ED) and an antisense region providing target specificity (Binding Domain, BD). In this study, we demonstrate that the invSINEB2 sequence from the natural SINEUP AS Uchl1 RNA is an Internal Ribosomal Entry Site (IRES) when acting in cis and that known viral and cellular IRES sequences can act as Effector Domain in synthetic SINEUPs. To identify natural IRES-containing, non-coding RNAs with SINEUP-like activity, we focused on circular RNAs showing that the non-coding circ5533, transcribed from the c-myc locus, enhances endogenous protein expression of its target PX Domain Containing Serine/Threonine Kinase Like (Pxk) by increasing mRNA association to polysomes. In summary, this study shows that natural and synthetic SINEUPs include linear and circular transcripts with an embedded IRES sequence as ED.

molecular biology↗

bioRxiv2023

Water chlorination increases the relative abundance of an antibiotic resistance marker in developing sourdough starters

Multiple factors explain the proper development of sourdough starters. While the role of raw ingredients and geography, among other things, have been widely studied recently, the possible effect of water chlorination on the overall bacterial communities associated with sourdough remains to be explored. Here, using 16s rRNA amplicon sequencing, we show that water chlorination at levels commonly found in drinking water systems has a limited impact on the overall bacterial communities developing in sourdough starters. However, using targeted sequencing, we found that the abundance of integron 1, a genetic mechanism responsible for the horizontal exchange of antibiotic resistance genes in spoilage and pathogenic bacteria, increased significantly with the level of water chlorination. While our results suggest that water chlorination might not impact sourdough starters at a deep phylogenetic level, they indicate that it can favor the growth of key spoilage bacteria.

microbiology↗

bioRxiv2022

Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral and transcriptomic levels

Many neurodevelopmental conditions, including autism, affect males more than females. Genomic mechanisms enhancing risk in males may contribute to this sex-bias. The ubiquitin protein ligase E3A gene (Ube3a) exerts pleiotropic effects on cellular homeostasis via control of protein turnover and by acting as transcriptional coactivator with steroid hormone receptors. Overdosage of Ube3a via duplication or triplication of chromosomal region 15q11-13 causes 1-2% of autistic cases. Here, we test the hypothesis that increased dosage of Ube3a may influence autism-relevant phenotypes in a sex-biased manner. We report robust sex-biasing effects on brain connectomics and repetitive behaviors in mice with extra copies of Ube3a. These effects were associated with a profound transcriptional dysregulation of several known autism-associated genes (e.g., FMR1, SCN2A, PTEN, MEF2C, SHANK3, TSC2) as well as differentially-expressed genes identified in human 15q duplication and in autistic patients. Notably, increased Ube3a dosage also affects multiple sex-relevant mechanisms, including genes on the X chromosome, genes influenced by sex steroid hormones, downstream targets of the androgen and estrogen receptors, or genes that are sex-differentially regulated by transcription factors. These results suggest that Ube3a overdosage can critically contribute to sex-bias in neurodevelopmental conditions via influence on sex-differential mechanisms.

neuroscience↗

bioRxiv2022

Regulation of TRIB1 abundance in hepatoma models

Tribbles related homolog 1 (TRIB1) contributes to lipid and glucose homeostasis by facilitating the degradation of cognate cargos by the proteasome. We previously reported that TRIB1 was unstable in non-hepatic cellular models. Moreover, inclusion of proteasome inhibitors failed to prevent TRIB1 loss, consistent with the involvement of proteasome independent degradative processes. In view of the key role of TRIB1 in liver function, we continue our exploration of TRIB1 regulation pathways in two commonly used human hepatocyte models, HuH-7 and HepG2 cells. Proteasome inhibitors potently upregulated both endogenous and recombinant TRIB1 mRNA and protein levels. Increased transcript abundance was independent of MAPK activation while ER stress was a relatively mild inducer. Despite increasing TRIB1 protein abundance and stabilizing bulk ubiquitination, proteasome inhibition failed to stabilize TRIB1, pointing to the predominance of proteasome independent protein degradation processes controlling TRIB1 protein abundance in hepatomas. Proteasome inhibition via downregulation of its PSMB3 regulatory subunit, in contrast to its chemical inhibition, had minimal impact on TRIB1 levels. Moreover, immunoprecipitation experiments showed no evidence of TRIB1 ubiquitination. Cytoplasmic retained TRIB1 was unstable, indicating that TRIB1 lability is regulated prior to its nuclear import. Substitution of the TRIB1 PEST-like region with a GST helical region or N-terminal deletions failed to fully stabilize TRIB1. Finally, inclusion of protease or autophagy inhibitors in vivo did not rescue TRIB1 stability. This work excludes proteasome-mediated degradation as a significant contributor to TRIB1 instability and identifies transcriptional regulation as a prominent mechanism regulating TRIB1 abundance in liver models in response to proteasome inhibition.

cell biology↗

bioRxiv2021

A common polymorphism that protects from cardiovascular disease increases fibronectin processing and secretion

BackgroundFibronectin (FN1) is an essential regulator of homodynamic processes and tissue remodeling which has been proposed to contribute to atherosclerosis. Moreover, recent large scale genome wide association studies have linked common genetic variants within the FN1 gene to coronary artery disease (CAD) risk. MethodsPublic databases were analyzed by two-Sample Mendelian Randomization. Expression constructs encoding short FN1 reporter constructs and full-length plasma FN1, differing in the polymorphism, were designed and introduced in various cell models. Secreted and cellular levels were then analyzed and quantified by SDS-PAGE and fluorescence approaches. Mass spectrometry and glycosylation analyses were performed to probe possible post-transcriptional differences. ResultsHigher FN1 protein levels in plasma associates with a reduced risk of cardiovascular disease. Moreover, common CAD risk SNPs in the FN1 locus associate with circulating levels of FN1. This region is shown to encompass a L15Q polymorphism within the FN1 signal peptide. The presence of the minor allele that predisposes to CAD, corresponding to the Q15 variant, alters glycosylation and reduces FN1 secretion in a direction consistent with the bioinformatic analyses. ConclusionIn addition to providing novel functional evidence implicating FN1 as a protective force in cardiovascular disease, these findings demonstrate that a common variant within a secretion signal peptide regulates protein function.

biochemistry↗

bioRxiv2020

Structure-based design of hepatitis C virus E2 glycoprotein improves serum binding and cross-neutralization

An effective vaccine for hepatitis C virus (HCV) is a major unmet need, and it requires an antigen that elicits immune responses to key conserved epitopes. Based on structures of antibodies targeting HCV envelope glycoprotein E2, we designed immunogens to modulate the structure and dynamics of E2 and favor induction of bNAbs in the context of a vaccine. These designs include a point mutation in a key conserved antigenic site to stabilize its conformation, as well as redesigns of an immunogenic region to add a new N-glycosylation site and mask it from antibody binding. Designs were experimentally characterized for binding to a panel of human monoclonal antibodies (HMAbs) and the coreceptor CD81 to confirm preservation of epitope structure and preferred antigenicity profile. Selected E2 designs were tested for immunogenicity in mice, with and without hypervariable region 1, which is an immunogenic region associated with viral escape. One of these designs showed improvement in polyclonal immune serum binding to HCV pseudoparticles and neutralization of isolates associated with antibody resistance. These results indicate that antigen optimization through structure-based design of the envelope glycoproteins is a promising route to an effective vaccine for HCV.

microbiology↗

bioRxiv2020

Aberrant synaptic release underlies sleep/wake transition deficits in a mouse Vamp2 mutant

Sleep-wake transitions are modulated through extensive subcortical networks although the precise roles of their individual components remain elusive. Using forward genetics and in vivo electrophysiology, we identified a recessive mouse mutant line characterised by a reduced propensity to transition between all sleep states while a profound loss in total REM sleep time was evident. The causative mutation, an Ile102Asn substitution in VAMP2, was associated with substantial synaptic changes while in vitro electrophysiological investigations with fluorescence imaging revealed a diminished probability of vesicular release in mutants. We conclude that the synaptic efficiency of the entire subcortical brain network determines the likelihood that an animal transitions from one vigilance state to the next.

neuroscience↗

bioRxiv2019

RNA binding kinase UHMK1 regulates therapy induced metabolic adaptation in BRAFV600 melanoma

Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by a residual disease that results in relapse. This residual disease is characterized by drug-induced adaptation, that in melanoma includes altered metabolism. Here, we examined how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNAi screen and global gene expression profiling. This systematic approach revealed post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA binding kinase UHMK1 interacts with mRNAs that encode metabolic proteins and selectively controls their transport and translation during adaptation to BRAF targeted therapy. Inactivation of UHMK1 improves metabolic response to BRAF targeted therapy and delays resistance to BRAF and MEK combination therapy in vivo. Our data support a model wherein post-transcriptional gene expression pathways regulate metabolic adaptation underpinning targeted therapy response and suggest inactivation of these pathways may delay disease relapse.

cancer biology↗