Ben Lai | University of British Columbia (original) (raw)

Papers by Ben Lai

Journal of Heredity, Jan 15, 2010

The impact of female reproductive success on the mating system, gene flow, and genetic diversity ... more The impact of female reproductive success on the mating system, gene flow, and genetic diversity of the filial generation was studied using a random sample of 801 bulk seed from a 49-clone Pseudotsuga menziesii seed orchard. We used microsatellite DNA fingerprinting and pedigree reconstruction to assign each seed's maternal and paternal parents and directly estimated clonal reproductive success, selfing rate, and the proportion of seed sired by outside pollen sources. Unlike most family array mating system and gene flow studies conducted on natural and experimental populations, which used an equal number of seeds per maternal genotype and thus generating unbiased inferences only on male reproductive success, the random sample we used was a representative of the entire seed crop; therefore, provided a unique opportunity to draw unbiased inferences on both female and male reproductive success variation. Selfing rate and the number of seed sired by outside pollen sources were found to be a function of female fertility variation. This variation also substantially and negatively affected female effective population size. Additionally, the results provided convincing evidence that the use of clone size as a proxy to fertility is questionable and requires further consideration.

bioRxiv (Cold Spring Harbor Laboratory), Dec 28, 2020

Transcriptome-Wide Association Studies discover SNP effects mediated by gene expression through a... more Transcriptome-Wide Association Studies discover SNP effects mediated by gene expression through a twostage process: a typically small reference panel is used to infer SNP-expression effects, and then these are applied to discover associations between imputed expression and phenotypes. We investigate whether the accuracy of SNP-expression and expression-phenotype associations can be increased by performing inference on both the reference panel and independent GWAS cohorts simultaneously. We develop EMBER (Estimation of Mediated Binary Effects in Regression) to re-estimate these effects using a liability threshold model with an adjustment to variance components accounting for imputed expression from GWAS data. In simulated data with only gene-mediated effects, EMBER more than doubles the performance of SNP-expression linear regression, increasing mean r 2 from 0.3 to 0.65 with a gene-mediated variance explained of 0.01. EMBER also improves estimation accuracy when the fraction of cis-SNP variance mediated by genes is as low as 30%. We apply EMBER to genotype and gene expression data in schizophrenia by combining 512 samples from the CommonMind Consortium and 56,081 samples from the Psychiatric Genomic Consortium. We evaluate performance of EMBER in 36 genes suggested by TWAS by concordance of inferred effects with effects reported independently for frontal cortex expression. Applying the EMBER framework to a baseline linear regression model increases performance in 26 out of 36 genes (sign test p-value .0020) with an increase in mean r 2 from 0.200 to 0.235. 2 Introduction Genome-wide association methods have to date discovered thousands of associations with disease risks and other phenotypes [1]. However, functional studies to determine the causal genes or mechanisms behind these 1 .

Science

Fine-tuning of protein-protein interactions occurs naturally through coevolution, but this proces... more Fine-tuning of protein-protein interactions occurs naturally through coevolution, but this process is difficult to recapitulate in the laboratory. We describe a platform for synthetic protein-protein coevolution that can isolate matched pairs of interacting muteins from complex libraries. This large dataset of coevolved complexes drove a systems-level analysis of molecular recognition between Z domain–affibody pairs spanning a wide range of structures, affinities, cross-reactivities, and orthogonalities, and captured a broad spectrum of coevolutionary networks. Furthermore, we harnessed pretrained protein language models to expand, in silico, the amino acid diversity of our coevolution screen, predicting remodeled interfaces beyond the reach of the experimental library. The integration of these approaches provides a means of simulating protein coevolution and generating protein complexes with diverse molecular recognition properties for biotechnology and synthetic biology.

Designing protein with desirable structure and functional properties is the pinnacle of computati... more Designing protein with desirable structure and functional properties is the pinnacle of computational protein design with unlimited potentials in the scientific community from therapeutic development to combating the global climate crisis. However, designing protein macromolecules at scale remains challenging due to hard-to-realize structures and low sequence design success rate. Recently, many generative models are proposed for protein design but they come with many limitations. Here, we present a VAE-based universal protein structure generative model that can model proteins in a large fold space and generate high-quality realistic 3-dimensional protein structures. We illustrate how our model can enable robust and efficient protein design pipelines with generated conformational decoys that bridge the gap in designing structure conforming sequences. Specifically, sequences generated from our design pipeline outperform native fixed backbone design in 856 out of the 1,016 tested targe...

In this work, we establish a framework to tackle the inverse protein design problem; the task of ... more In this work, we establish a framework to tackle the inverse protein design problem; the task of predicting a protein’s primary sequence given its backbone conformation. To this end, we develop a generative SE(3)-equivariant model which significantly improves upon existing autoregressive methods. Conditioned on backbone structure, and trained with our novel partial masking scheme and side-chain conformation loss, we achieve state-of-the-art native sequence recovery on structurally independent CASP13, CASP14, CATH4.2, and TS50 test sets. On top of accurately recovering native sequences, we demonstrate that our model captures functional aspects of the underlying protein by accurately predicting the effects of point mutations through testing on Deep Mutational Scanning datasets. We further verify the efficacy of our approach by comparing with recently proposed inverse protein folding methods and by rigorous ablation studies.

Free Radical Biology and Medicine, May 20, 2021

Early treatment can prevent the occurrence of diabetes; however, there are few pharmacological tr... more Early treatment can prevent the occurrence of diabetes; however, there are few pharmacological treatment strategies to date. The liver is a major metabolic organ, and hepatic glucose homeostasis is dysregulated in type 1 and type 2 diabetes mellitus. However, the potential of specifically targeting the liver to prevent diabetes has not been fully exploited. In this study, we found that compartmentally inhibiting hepatic oxidants by nano-MitoPBN, a liver mitochondrial-targeting ROS scavenger, could effectively prevent diabetes. Our results demonstrated that nano-MitoPBN reversed the downregulation of PGC-1α and the enhanced gluconeogenesis in the livers of diabetic mice. PGC-1α, through an AMPK- and SIRT3-mediated mechanism, promoted mitochondrial biogenesis, increased the number of mitochondria, and enhanced the rate of aerobic oxidation, leading to decreased glucose levels in the blood by increasing glucose uptake and catabolism in the liver. Moreover, the increase in PGC-1α activity did not promote the activation of gluconeogenesis. Our study demonstrated that by regulating the redox balance of liver mitochondria in the early stage of diabetes, PGC-1α could selectively inhibit gluconeogenesis in the liver and promote hepatic mitochondrial function, which accelerated the catabolism of hepatic glucose and reduced blood glucose. Thus, glucose tolerance can be normalized through only three weeks of intervention. Our results showed that nano-MitoPBN could effectively prevent diabetes in a short period of time, highlighting the effectiveness and importance of early intervention for diabetes and suggesting the potential advantages of hepatic mitochondrial targeting oxidants nano-inhibitors in the prevention and early treatment of diabetes.

IEEE Transactions on Antennas and Propagation, 2021

Free Radical Research, 2021

Abstract Reactive oxygen species (ROS) has been implicated as a contributor to both the onset and... more Abstract Reactive oxygen species (ROS) has been implicated as a contributor to both the onset and the progression of diabetes, however how does redox state affect diabetes has not been fully understood. Here we study the role of redox interference on pancreatic mitochondria and the progression of diabetes. We applied streptozotocin (STZ) to establish diabetes mellitus (DM) model in rats, applied FeSO4 to produce oxidative stress (OS) and Ganoderma lucidum polysaccharides as antioxidant intervention (AO). Our results showed that in OS and DM group, oxidative stress caused the imbalance of redox state, resulting in higher lipid peroxidation level and lower antioxidant level, while AO treatment group reduced blood glucose by repairing the redox balance. The insulin level has the order of Normal Control (NC)<AO < DM < OS, suggesting oxidative stress promoted insulin secretion in a compensatory mechanism. The Mn-SOD expression in OS groups of pancreas were significantly lower than other groups, while the p53 expression was significantly higher. The mitochondrial ultrastructure of pancreatic β cells were impaired in DM group, and the damage was more severe in OS group, paralleled with significantly reduced secretory granules, both of which were repaired in the AO group. Our results demonstrated that the redox state can affect the blood glucose of diabetic rats, and oxidative stress can aggravate diabetes, while the early antioxidant treatment can alleviate the process of diabetes through reversing the imbalance of redox state and repairing the pancreatic mitochondria. These results suggest that redox balance plays an important role in the treatment of diabetes.

bioRxiv, 2020

Reconstruction of the complete degloving injury of the hand is a difficult problem in plastic and... more Reconstruction of the complete degloving injury of the hand is a difficult problem in plastic and reconstructive surgery. Many reconstructive options including skin graft, regional flap, distant flap or free flap have been tried to salvage the denuded skin of the fingers and hand. However, the functional and cosmetic results are as yet not satisfactory. We present a case of a complete degloved hand initially treated with skin grafting, and then with a delayed free toe flap for the thumb and free web-space flap for two opposable fingers to provide tripod pinch. The final result was satisfied both functionally and cosmetically.

Free Radical Biology and Medicine, 2021

Scientific Reports, 2018

Seed orchards main function is delivering breeding programs’ gains in the form of genetically imp... more Seed orchards main function is delivering breeding programs’ gains in the form of genetically improved seedlings. They are unique experimental populations, perfectly suited for studying various pollination environments (natural or otherwise), affecting their mating system parameters. Here, under different pollination environment (natural and intrusive (pollen augmentation and/or bloom-delay)), the mating system of a second generation, wind-pollinated, coastal Douglas-fir (Pseudotsuga menziesii var. menziesii (Mirb.) Franco) seed orchard was evaluated over four years. Using DNA microsatellite markers and bulk seed samples, we conducted pedigree reconstruction to assign each seed’s male and female parents, followed by determining the extent of pollen contamination (external gene flow), selfing rate, and, parental gametic contribution for each year. Overall, external pollen contamination rates ranged between 10 and 28%, selfing rate varied between 12 and 17%, and 80% of the seed crops ...

Advanced healthcare materials, Jan 16, 2017

Significant advances in biomaterials, stem cell biology, and microscale technologies have enabled... more Significant advances in biomaterials, stem cell biology, and microscale technologies have enabled the fabrication of biologically relevant tissues and organs. Such tissues and organs, referred to as organ-on-a-chip (OOC) platforms, have emerged as a powerful tool in tissue analysis and disease modeling for biological and pharmacological applications. A variety of biomaterials are used in tissue fabrication providing multiple biological, structural, and mechanical cues in the regulation of cell behavior and tissue morphogenesis. Cells derived from humans enable the fabrication of personalized OOC platforms. Microscale technologies are specifically helpful in providing physiological microenvironments for tissues and organs. In this review, biomaterials, cells, and microscale technologies are described as essential components to construct OOC platforms. The latest developments in OOC platforms (e.g., liver, skeletal muscle, cardiac, cancer, lung, skin, bone, and brain) are then discuss...

Acta Crystallogr E Struct Rep, 2004

INTRODUCTION: Trauma-informed care (TIC) is an approach in which mental health agencies recognize... more INTRODUCTION: Trauma-informed care (TIC) is an approach in which mental health agencies recognize the pervasive impact of trauma and aim to ameliorate rather than exacerbate its effects. The curriculum-based Risking Connection (RC) trauma training program is one of several models used nationally and internationally as a pathway toward TIC culture change in child residential settings. Our previous research has demonstrated that RC increases staff knowledge about RC and staff beliefs and behavior favorable to TIC. RC also aims to improve professional quality of life, including burn out (BO), secondary traumatic stress (STS), and compassion satisfaction (CS), or the pleasure staff derive from being able to do their work well (Stamm, 2005). The purpose of this study is 1) to replicate and 2) to better understand the implementation of TIC via RC trauma training for staff at a rural mental health agency in Northwest Canada. METHOD: Congregate care staff (N = 67, ages 24 to 66, M = 39.80, ...

Proceedings of 2014 3rd Asia-Pacific Conference on Antennas and Propagation, 2014

The characteristic basis function method is applied to analyze the radiation and scattering probl... more The characteristic basis function method is applied to analyze the radiation and scattering problems of waveguide array with longitudinal slots in the broad wall. By using the geometry characteristic of the waveguide slot array, the equivalent magnetic currents are modeled on the slot surfaces, and the characteristic basis functions are established on each slot separately. Compared with the existing method of moments solution which is used for analyzing the slot array, the new method can greatly reduce the number of unknowns, and the memory and computation costs in solving the matrix equation can be greatly saved. The numerical results show that only one characteristic basis function is needed to be constructed for each slot, and the number of unknowns is only the number of array elements. Accordingly, the proposed method can be used to analyze the large waveguide slot array more efficiently.

New Phytologist, 2012

Summary The increasing ecological and economical importance of Populus species and hybrids has st... more Summary The increasing ecological and economical importance of Populus species and hybrids has stimulated research into the investigation of the natural variation of the species and the estimation of the extent of genetic control over its wood quality traits for traditional forestry activities as well as the emerging bioenergy sector. A realized kinship matrix based on informative, high‐density, biallelic single nucleotide polymorphism (SNP) genetic markers was constructed to estimate trait variance components, heritabilities, and genetic and phenotypic correlations. Seventeen traits related to wood chemistry and ultrastructure were examined in 334 9‐yr‐old Populus trichocarpa grown in a common‐garden plot representing populations spanning the latitudinal range 44° to 58.6°. In these individuals, 9342 SNPs that conformed to Hardy–Weinberg expectations were employed to assess the genomic pair‐wise kinship to estimate narrow‐sense heritabilities and genetic correlations among traits. ...

Mobile Networks and Applications, 2014

Journal of Heredity, 2010