Biology subjects

Lau, M.

Publications and source records attributed to Lau, M..

6 recordsLinked to original sources

bioRxiv2026

Structural Basis of Electron Transfer by the Human Nitric Oxide Synthase Holoenzyme Complex

Mammalian nitric oxide synthase (NOS) generates nitric oxide (NO), an essential signaling molecule in neurotransmission, inflammation, and cardiovascular regulation. NOS dysregulation contributes to neurodegeneration, septic shock, and ischemia. The structural basis of NOS function remains unclear, likely due to its dynamic, multi-component architecture. Catalysis requires electron transfer across five cofactors, with the oxygenase (Oxy) domain converting L-arginine to NO after receiving electrons from the reductase (Red) domain via calmodulin (CaM) activation. Here, we report cryo-electron microscopy structures of the human inducible NOS:CaM holoenzyme, revealing a previously unresolved architecture in which the Red:CaM arm spans the Oxy dimer in an apparent active state for cross-monomer electron transfer. The FMN subdomain is rotated [~]90{degrees} relative to the Red core, positioning its cofactor [~]9 [A] from the heme, adjacent to a conserved aromatic residue within a narrow Oxy domain tunnel. Red-Oxy flexibility in the active state may facilitate electron shuttling among cofactors, defining how NOS cofactors are transiently aligned to enable catalysis.

biochemistry↗

bioRxiv2023

Biodesign of Frugal CRISPR Kits for Equitable and Accessible Education

Equitable and accessible education on life sciences and bioengineering is crucial to training the next generation of scientists, fostering transparency in public decision-making, and ensuring biotechnology democratization that can benefit a wide-ranging population. As a ground-breaking technology for genome engineering, CRISPR has transformed research and therapeutics. However, hands-on exposure to this technology for educational purposes has remained restricted, primarily due to extensive resources required to execute CRISPR experiments. In this study, we develop an accessible and frugal CRISPR kit, tailored for K-12 education settings. Our CRISPR kit eliminates the need for equipment, prioritizes biosafety, and utilizes cost-effective reagents. By combining CRISPRi gene regulation, chromoproteins, cell-free transcription-translation systems, and smartphone-based quantification, our kit offers a user-friendly approach and a reliable assessment of CRISPR activity, eliminating the need for a traditional laboratory setup. Experiments conducted by high school students in real-world settings highlight the kits utility for conducting reliable CRISPR experiments. The frugal CRISPR kit provides a modular and expandable platform to offer hands-on experience in genome engineering, and will facilitate equitable and accessible education and technology democratization for communities of diverse socioeconomic and geographic backgrounds.

bioengineering↗

bioRxiv2022

Effects of breast fibroepithelial tumor associated retinoic acid receptor alpha ligand binding domain mutations on receptor function and retinoid signaling

Point mutations in the ligand binding domain of retinoic acid receptor alpha (RAR) have been implicated in breast fibroepithelial tumors development. However, their role in the tumorigenesis of solid tumors is currently unknown. In this study, using a combination of biochemical and cellular assays, we evaluated the functional consequences of known tumor associated RAR mutations on retinoic acid signaling. All of the clinically associated mutants tested showed diminished transcriptional activities compared to wild type RAR. These mutants also exhibited a dominant negative effect, an activity which has previously been linked to developmental defects and tumor formation in mice. X-ray crystallography showed that mutants remain relatively intact structurally and the loss of transcriptional activity is due to altered co-activator recruitment. In agreement with our biochemical analyses, transcriptomics and cell growth analysis showed that the mutant RAR proteins confer resistance to growth inhibition in the presence of its ligand in phyllodes tumor cells. Although the mutations impair the receptor responses to retinoic acid, certain mutant RAR are partially reactivatable with alternative synthetic agonists. Our data provide insights into the mechanisms by which RAR mutations impact tumorigenesis.

cancer biology↗

bioRxiv2022

Anoxic age as a new tool to predict biogeochemical consequences of oxygen depletion in lakes

Lake deoxygenation is of growing concern because it threatens ecosystem services delivery. Complete deoxygenation, anoxia, is projected to prolong and expand in lakes, promoting the production or release of nutrients, greenhouse gases and metals from water column and the sediments. Accumulation of these compounds cannot be easily predicted thus hindering our capacity to forecast the ecological consequences of global changes on aquatic ecosystems. Here, we used lakes Arendsee and Mendota monitoring data to develop a novel metric, anoxic age, characterizing lake hypolimnetic anoxia. Anoxic age explained, as a single predictor, 44% to 58% of the variation for ammonium, soluble reactive phosphorus and a dissolved organic matter fluorophore. Anoxic age could be modelled using only two oxygen profiles and lake bathymetry, making it an easily applicable tool to interpret and extrapolate biogeochemical data. This novel metric thus has the potential to transform widely available oxygen profiles into an ecologically meaningful variable. Scientific Significance StatementOxygen depletion in deep water layers of lakes is of growing concern as it expands due to eutrophication and climate change. Anoxia is deleterious to benthic invertebrates and fishes, enables the production of potent greenhouse gases and releases stored phosphorus from sediments, among others. However, quantitatively forecasting the consequences of anoxia remains a challenge. Here, we developed a novel metric, anoxic age, which may be derived from oxygen profiles to predict end-of-summer concentration of various water chemical parameters. We argue that all by-products of anaerobic microbial metabolism should be related to anoxic age as they are released or processed continuously during anoxia. We believe that anoxic age can be used to predict the ecological consequences of temporally and spatially growing anoxia.

ecology↗

bioRxiv2019

Wheat VRN1 and FUL2 play critical and redundant roles in spikelet meristem identity and spike determinacy

The spikelet is the basic unit of the grass inflorescence. In this study, we show that wheat MADS-box genes VRN1, FUL2 and FUL3 play critical and redundant roles in spikelet and spike development, and also affect flowering time and plant height. In the vrn1ful2ful3-null triple mutant, the inflorescence meristem formed a normal double-ridge structure, but then the lateral meristems generated vegetative tillers subtended by leaves instead of spikelets. These results suggest an essential role of these three genes in the determination of spikelet meristem identity and the suppression of the lower ridge. Inflorescence meristems of vrn1ful2ful3-null and vrn1ful2-null remained indeterminate and single vrn1-null and ful2-null mutants showed delayed formation of the terminal spikelet and increased number of spikelets per spike. Moreover, the ful2-null mutant showed more florets per spikelet, which together with a higher number of spikelets, resulted in a significant increase in the number of grains per spike in the field. Our results suggest that a better understanding of the mechanisms underlying wheat spikelet and spike development can inform future strategies to improve grain yield in wheat.\n\nSUMMARY STATEMENTThe wheat MADS-box proteins VRN1, FUL2 and FUL3 play critical and overlapping roles in the development of spikelets, which are the basic unit of all grass inflorescences.

developmental biology↗

bioRxiv2018

Expanded view of the ecological genomics of ant responses to climate change

Given the abundance, broad distribution, and diversity of roles that ants play in many ecosystems, they are an ideal group to serve as ecosystem indicators of climatic change. At present, only a few whole-genome sequences of ants are available (19 of > 16,000 species), mostly from tropical and sub-tropical species. To address this limited sampling, we sequenced genomes of temperate-latitude species from the genus Aphaenogaster, a genus with important seed dispersers. In total, we sampled seven colonies of six species: A. ashmeadi, A. floridana, A. fulva, A. miamiana, A. picea, and A. rudis. The geographic ranges of these species collectively span eastern North America from southern Florida to southern Canada, which encompasses a latitudinal gradient in which many climatic variables are changing rapidly. For the six genomes, we assembled an average of 271,039 contigs into 47,337 scaffolds. The mean genome size was 370.5 Mb, ranging from 310.3 to 429.7, which is comparable to that of other sequenced ant genomes (212.8 to 396.0 Mb) and flow cytometry estimates (210.7 to 690.4 Mb). In an analysis of currently sequenced ant genomes and the new Aphaenogaster sequences, we found that after controlling for both spatial autocorrelation and phylogenetics ant genome size was marginally correlated with sample site climate similarity. Of all examined climate variables, minimum temperature showed the strongest correlation with genome size, with ants from locations with colder minimum temperatures having larger genomes. These results suggest that temperature extremes could be a selective force acting on ant genomes and point to the need for more extensive sequencing of ant genomes.

genomics↗