William Hwang - Academia.edu (original) (raw)

Papers by William Hwang

Clinical Cancer Research, 2021

Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy in urgent need of a ... more Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy in urgent need of a molecular framework for guiding therapeutic strategies. Bulk transcriptomic efforts over the past decade have yielded two broad consensus subtypes: classical pancreatic/epithelial versus basal-like/squamous/quasi-mesenchymal. Although this binary classification enables prognostic stratification, it does not currently inform the administration of treatments uniquely sensitive to either subtype. Furthermore, bulk mRNA studies are challenged by distinguishing contributions from the neoplastic compartment versus other cell types in the microenvironment, which is accentuated in PDAC given that neoplastic cellularity can be low. The application of single-cell transcriptomics to pancreatic tumors has generally lagged behind other cancer types due in part to the difficulty of extracting high-quality RNA from enzymatically degradative tissue, but emerging studies have and will continue to shed li...

JCO Oncology Practice, 2020

Biophysical Journal, 2016

The SWI/SNF-family remodelers regulate chromatin structure by coupling the free energy from ATP h... more The SWI/SNF-family remodelers regulate chromatin structure by coupling the free energy from ATP hydrolysis to the repositioning and restructuring of nucleosomes, but how the ATPase activity of these enzymes drives the motion of DNA across the nucleosome remains unclear. Here, we used single-molecule FRET to monitor the remodeling of mononucleosomes by the yeast SWI/SNF remodeler, RSC. We observed that RSC primarily translocates DNA around the nucleosome without substantial displacement of the H2A-H2B dimer. At the sites where DNA enters and exits the nucleosome, the DNA moves largely along or near its canonical wrapping path. The translocation of DNA occurs in a stepwise manner, and at both sites where DNA enters and exits the nucleosome, the step size distributions exhibit a peak at approximately 1-2 bp. These results suggest that the movement of DNA across the nucleosome is likely coupled directly to DNA translocation by the ATPase at its binding site inside the nucleosome.

IEEE International Conference on Test, 2005.

Microfluidics-based biochips are soon expected to revolutionize biosensing, clinical diagnostics ... more Microfluidics-based biochips are soon expected to revolutionize biosensing, clinical diagnostics and drug discovery. Robust off-line and on-line test techniques are required to ensure system dependability as these biochips are deployed for safety-critical applications. Due to the underlying mixed-technology and mixed-energy domains, biochips exhibit unique failure mechanisms and defects. We first relate some realistic defects to fault models and observable errors. We next set up an experiment to evaluate the manifestations of electrode-short faults. Motivated by the experimental results, we present a testing and diagnosis methodology to detect catastrophic faults and locate faulty regions. The proposed method is evaluated using a biochip performing real-life multiplexed bioassays.

Optics Express, 2006

Existing darkfield illumination schemes are incompatible with many types of samples and/or proced... more Existing darkfield illumination schemes are incompatible with many types of samples and/or procedures. We present a darkfield epi-illumination scheme which addresses these incompatibilities by providing illumination through the imaging objective. We validate the system performance using silver nanospheres in varying refractive index environments, characterize the intensity distribution of the darkfield illumination, and demonstrate system capabilities through a preliminary study of functionalized gold nanosphere interactions with cancer cells in culture. We observe a broadened scattering spectrum from unconjugated nanoparticles, as compared with anti-EGFR conjugated nanoparticles, upon incubation with cancer cells, and discuss the implications of this observation.

Nature Nanotechnology, 2009

Molecular BioSystems, 2008

Journal of Electronic Testing, 2007

International Congress Series, 2004

We survey swarm intelligence from microorganisms (bacteria phenol/genotypes of Myxococcus xanthus... more We survey swarm intelligence from microorganisms (bacteria phenol/genotypes of Myxococcus xanthus, and marine light quorum sensing in V. fischeri) to colonizing insects (ants, bees, termites) and flocking animals (pelicans). All seem to rely on some sensors for communication including local chemical pheromone secretions. We conclude that swarming robots prefer to operate at the equilibrium, at minimum free energy H = E À T o S, in cases of truly unsupervised learning among teammates without constant attention of human master.

Biophysical Journal, 2013

is catalysed by AddAB helicase-nuclease complexes; motor proteins that unwind the DNA duplex and ... more is catalysed by AddAB helicase-nuclease complexes; motor proteins that unwind the DNA duplex and degrade the nascent single-strands in a manner regulated by specific single-stranded DNA sequences called Chi recombination hotspots (Yeeles and Dillingham, 2007; Yeeles et al., 2011). We have used Magnetic Tweezers to investigate the real-time dynamics of AddAB translocation on dsDNA and the effect of recombination hotspot recognition on this process. AddAB translocation traces showed a complex appearance with variable velocities between 200-400 bp/s at room temperature. We found that AddAB was prone to stochastic pausing in areas which contained many Chi-like sequences. Experiments using an AddAB mutant that is unable to recognize Chi strongly suggest that this pausing is due to transient recognition of Chi-like sequences and highlight the antagonistic nature of DNA translocation and sequence specific DNA recognition activities. Experiments using substrates containing bona fide Chi sequences showed that AddAB also pauses at Chi, but these events are longer and not exponentially distributed, suggesting a multistep process. We propose a model for the recognition of Chi and Chi-like sequences to explain the origins of this pausing behavior during failed or successful hotspot recognition.

Biophysical Journal, 2009

DNA in eukaryotic cells is organized hierarchically in chromatin. The vital life processes of DNA... more DNA in eukaryotic cells is organized hierarchically in chromatin. The vital life processes of DNA transcription, replication and repair, and the pathological progression of cancer and viral infection occur in the context of chromatin. Nucleosomes, the fundamental repeating units of chromatin, are actively positioned along DNA by ATP-dependent, chromatin remodeling factors. We have solved the X-ray structure of the ISW1a(DATPase) remodeling factor from the yeast, S. cerevisiae. ISW1a is a member of the ISWI family of remodeling factors and spaces nucleosomes in vivo to a repeat of~165 bp. Cryo-electron microscopy image analysis of ISW1a(DATPase) bound to nucleosomes suggests the regions of interaction between it and nucleosomes. Combined with solution data [1] and the modeled structure of the ATPase domain (homology with Sso [2] and Rad54 [3]), a tentative mechanism for nucleosome remodeling is proposed.

ACM Journal on Emerging Technologies in Computing Systems, 2007

Microfluidics-based biochips, also referred to as lab-on-a-chip, are devices that integrate fluid... more Microfluidics-based biochips, also referred to as lab-on-a-chip, are devices that integrate fluid-handling functions such as sample preparation, analysis, separation, and detection. This emerging technology combines electronics with biology to open new application areas such as point-of-care diagnosis, on-chip DNA analysis, and automated drug discovery. We propose a design automation method for pin-constrained biochips that manipulate nanoliter volumes of discrete droplets on a microfluidic array. In contrast to the direct-addressing scheme that has been studied thus far in the literature, we assign a small number of independent control pins to a large number of electrodes in the biochip, thereby reducing design complexity and product cost. The design procedure relies on a droplet-trace-based array partitioning scheme and an efficient pin assignment technique, referred to as the “Connect-5 algorithm.” The proposed method is evaluated using a set of multiplexed bioassays.

Proceedings of the Design Automation & Test in Europe Conference, 2006

same level of system-level CAD support that is now commonplace in the IC industry. Recent advance... more same level of system-level CAD support that is now commonplace in the IC industry. Recent advances in microfluidics are expected to lead to sensor systems for high-throughput biochemical analysis. CAD tools are needed to handle increased design complexity for such systems. Analogous to classical VLSI synthesis, a top-down design automation approach can shorten the design cycle and reduce human effort. We focus here on the droplet routing problem, which is a key issue in biochip physical design automation. We develop the first systematic droplet routing method that can be integrated with biochip synthesis. The proposed approach minimizes the number of cells used for droplet routing, while satisfying constraints imposed by throughput considerations and fluidic properties. A real-life biochemical application is used to evaluate the proposed method. Analogous to classical VLSI synthesis, a top-down system-level design automation approach can be used to relieve biochip users from the burden of manual optimization of assays and time-consuming hardware design. We can divide the synthesis procedure for a digital microfluidic biochip into two major phases, i.e., architectural-level synthesis and physical design. A behavioral model for a set of bioassays is first obtained from their laboratory protocols. Architectural-level synthesis is then used to generate a macroscopic structure of the biochip; this is analogous to a structural RTL model in electronic CAD [5]. Next, physical design creates the final layout of the biochip, consisting of the placement of microfluidic modules such as mixers and storage units, the routes that droplets take between different modules, and other geometrical details [6].

JAMA oncology, Jan 25, 2018

Prostate cancer with adverse pathological features (ie, pT3 and/or positive margins) after prosta... more Prostate cancer with adverse pathological features (ie, pT3 and/or positive margins) after prostatectomy may be managed with adjuvant radiotherapy (ART) or surveillance followed by early-salvage radiotherapy (ESRT) for biochemical recurrence. The optimal timing of postoperative radiotherapy is unclear. To compare the clinical outcomes of postoperative ART and ESRT administered to patients with prostate cancer with adverse pathological features. This multi-institutional, propensity score-matched cohort study involved 1566 consecutive patients who underwent postprostatectomy ART or ESRT at 10 US academic medical centers between January 1, 1987, and December 31, 2013. Propensity score 1-to-1 matching was used to account for covariates potentially associated with treatment selection. Data were collected from January 1 to September 30, 2016. Data analysis was conducted from October 1, 2016, to October 21, 2017. Freedom from postirradiation biochemical failure, freedom from distant metast...

Neuro-oncology, Jun 22, 2015

Risk stratification of meningiomas by histopathological grade alone does not reliably predict whi... more Risk stratification of meningiomas by histopathological grade alone does not reliably predict which patients will progress/recur after treatment. We sought to determine whether preoperative imaging and clinical characteristics could predict histopathological grade and/or improve prognostication of progression/recurrence (P/R). We retrospectively reviewed preoperative MR and CT imaging features of 144 patients divided into low-grade (2007 WHO grade I; n = 118) and high-grade (2007 WHO grades II/III; n = 26) groups that underwent surgery between 2002 and 2013 (median follow-up of 49 months). Multivariate analysis demonstrated that the risk factors most strongly associated with high-grade histopathology were male sex, low apparent diffusion coefficient (ADC), absent calcification, and high peritumoral edema. Remarkably, multivariate Cox proportional hazards analysis demonstrated that, in combination with extent of resection, ADC outperformed WHO histopathological grade for predicting w...

Journal of the American Chemical Society, 2008

Cell, 2013

ISWI-family enzymes remodel chromatin by sliding nucleosomes along DNA, but the nucleosome transl... more ISWI-family enzymes remodel chromatin by sliding nucleosomes along DNA, but the nucleosome translocation mechanism remains unclear. Here we use single-molecule FRET to probe nucleosome translocation by ISWI-family remodelers. Distinct ISWI-family members translocate nucleosomes with a similar stepping pattern maintained by the catalytic subunit of the enzyme. Nucleosome remodeling begins with a 7 bp step of DNA translocation followed by 3 bp subsequent steps toward the exit side of nucleosomes. These multi-bp, compound steps are comprised of 1 bp substeps. DNA movement on the entry side of the nucleosome occurs only after 7 bp of exit-side translocation, and each entry-side step draws in a 3 bp equivalent of DNA that allows three additional base pairs to be moved to the exit side. Our results suggest a remodeling mechanism with well-defined coordination at different nucleosomal sites featuring DNA translocation toward the exit side in 1 bp steps preceding multibp steps of DNA movement on the entry side.

Nature, Jan 14, 2014

Imitation switch (ISWI)-family remodelling enzymes regulate access to genomic DNA by mobilizing n... more Imitation switch (ISWI)-family remodelling enzymes regulate access to genomic DNA by mobilizing nucleosomes. These ATP-dependent chromatin remodellers promote heterochromatin formation and transcriptional silencing by generating regularly spaced nucleosome arrays. The nucleosome-spacing activity arises from the dependence of nucleosome translocation on the length of extranucleosomal linker DNA, but the underlying mechanism remains unclear. Here we study nucleosome remodelling by human ATP-dependent chromatin assembly and remodelling factor (ACF), an ISWI enzyme comprising a catalytic subunit, Snf2h, and an accessory subunit, Acf1 (refs 2, 11 - 13). We find that ACF senses linker DNA length through an interplay between its accessory and catalytic subunits mediated by the histone H4 tail of the nucleosome. Mutation of AutoN, an auto-inhibitory domain within Snf2h that bears sequence homology to the H4 tail, abolishes the linker-length sensitivity in remodelling. Addition of exogenous ...

Journal of the American Chemical Society, 2007