Sub-pixel resolving optofluidic microscope for on-chip cell imaging

We report the implementation of a fully on-chip, lensless, sub-pixel resolving optofluidic microscope (SROFM). The device utilizes microfluidic flow to deliver specimens directly across a complementary metal oxide semiconductor (CMOS) sensor to generate a sequence of low-resolution (LR) projection images, where resolution is limited by the sensor's pixel size. This image sequence is then processed with a pixel super-resolution algorithm to reconstruct a single high resolution (HR) image, where features beyond the Nyquist rate of the LR images are resolved. We demonstrate the device's capabilities by imaging microspheres, protist Euglena gracilis, and Entamoeba invadens cysts with sub-cellular resolution and establish that our prototype has a resolution limit of 0.75 microns. Furthermore, we also apply the same pixel super-resolution algorithm to reconstruct HR videos in which the dynamic interaction between the fluid and the sample, including the in-plane and out-of-plane rotation of the sample within the flow, can be monitored in high resolution. We believe that the powerful combination of both the pixel super-resolution and optofluidic microscopy techniques within our SROFM is a significant step forwards toward a simple, cost-effective, high throughput and highly compact imaging solution for biomedical and bioscience needs

Topological kink states at a tilt boundary in gated multi-layer graphene

The search for new realization of topologically protected edge states is an active area of research. We show that a tilt boundary in gated multi-layer graphene supports topologically protected gapless kink states, associated with quantum valley Hall insulator (QVH). We investigate such kink states from two perspectives: the microscopic perspective of a tight-binding model and an ab-initio calculation on bilayer, and the perspective of symmetry protected topological (SPT) states for general multi-layer. We show that a AB-BA bilayer tilt boundary supports gapless kink states that are undeterred by strain concentrated at the boundary. Further, we establish the kink states as concrete examples of edge states of {\it time-reversal symmetric} ${\mathbb Z}$-type SPT, protected by no valley mixing, electron number conservation, and time reversal $T$ symmetries. This allows us to discuss possible phase transitions upon symmetry changes from the SPT perspective. Recent experimental observations of a network of such tilt boundaries suggest that transport through these novel topological kink states might explain the long standing puzzle of sub-gap conductance. Further, recent observation of gap closing and re-opening in gated bi-layer might be the first example of a transition between two distinct SPT's: QVH and LAF.Comment: Improved a discussion of the structural aspects of the tilt boundary. Included a discussion of boundary condition dependence. Added new section on connection to experiment

A smartphone-based chip-scale microscope using ambient illumination

Portable chip-scale microscopy devices can potentially address various imaging needs in mobile healthcare and environmental monitoring. Here, we demonstrate the adaptation of a smartphone's camera to function as a compact lensless microscope. Unlike other chip-scale microscopy schemes, this method uses ambient illumination as its light source and does not require the incorporation of a dedicated light source. The method is based on the shadow imaging technique where the sample is placed on the surface of the image sensor, which captures direct shadow images under illumination. To improve the image resolution beyond the pixel size, we perform pixel super-resolution reconstruction with multiple images at different angles of illumination, which are captured while the user is manually tilting the device around any ambient light source, such as the sun or a lamp. The lensless imaging scheme allows for sub-micron resolution imaging over an ultra-wide field-of-view (FOV). Image acquisition and reconstruction are performed on the device using a custom-built Android application, constructing a stand-alone imaging device for field applications. We discuss the construction of the device using a commercial smartphone and demonstrate the imaging capabilities of our system

On-chip continuous monitoring of motile microorganisms on an ePetri platform

Self-imaging Petri dish platforms with microscopy resolution, which we term ‘ePetri’, can significantly streamline cell cultures and/or other longitudinal biological studies. In this paper, we demonstrate high-resolution imaging and long-term culture of motile microorganisms in a specialized ePetri platform by taking advantage of the inherent motion. By applying a super-resolution algorithm to a set of low-resolution images of the microorganisms as they move across the sensing area of a complementary metal oxide semiconductor (CMOS) image sensor chip, we can render an improved-resolution image of the microorganisms. We perform a longitudinal study of Euglena gracilis cultured in an ePetri platform, and image-based analysis on the motion and morphology of the cells. As a miniaturized and automated culture monitoring platform, this ePetri technology can greatly improve studies and experiments with motile microorganisms

High affinity binding of H3K14ac through collaboration of bromodomains 2, 4 and 5 is critical for the molecular and tumor suppressor functions of PBRM1.

Polybromo-1 (PBRM1) is an important tumor suppressor in kidney cancer. It contains six tandem bromodomains (BDs), which are specialized structures that recognize acetyl-lysine residues. While BD2 has been found to bind acetylated histone H3 lysine 14 (H3K14ac), it is not known whether other BDs collaborate with BD2 to generate strong binding to H3K14ac, and the importance of H3K14ac recognition for the molecular and tumor suppressor function of PBRM1 is also unknown. We discovered that full-length PBRM1, but not its individual BDs, strongly binds H3K14ac. BDs 2, 4, and 5 were found to collaborate to facilitate strong binding to H3K14ac. Quantitative measurement of the interactions between purified BD proteins and H3K14ac or nonacetylated peptides confirmed the tight and specific association of the former. Interestingly, while the structural integrity of BD4 was found to be required for H3K14ac recognition, the conserved acetyl-lysine binding site of BD4 was not. Furthermore, simultaneous point mutations in BDs 2, 4, and 5 prevented recognition of H3K14ac, altered promoter binding and gene expression, and caused PBRM1 to relocalize to the cytoplasm. In contrast, tumor-derived point mutations in BD2 alone lowered PBRM1\u27s affinity to H3K14ac and also disrupted promoter binding and gene expression without altering cellular localization. Finally, overexpression of PBRM1 variants containing point mutations in BDs 2, 4, and 5 or BD2 alone failed to suppress tumor growth in a xenograft model. Taken together, our study demonstrates that BDs 2, 4, and 5 of PBRM1 collaborate to generate high affinity to H3K14ac and tether PBRM1 to chromatin. Mutations in BD2 alone weaken these interactions, and this is sufficient to abolish its molecular and tumor suppressor functions

A class of optimal state-delay control problems

We consider a general nonlinear time-delay system with state-delays as control variables. The problem of determining optimal values for the state-delays to minimize overall system cost is a non-standard optimal control problem – called an optimal state-delay control problem – that cannot be solved using existing optimal control techniques. We show that this optimal control problem can be formulated as a nonlinear programming problem in which the cost function is an implicit function of the decision variables. We then develop an efficient numerical method for determining the cost function’s gradient. This method, which involves integrating an auxiliary impulsive system backwards in time, can be combined with any standard gradient-based optimization method to solve the optimal state-delay control problem effectively. We conclude the paper by discussing applications of our approach to parameter identification and delayed feedback control