Lingyan Shi

University of California, San Diego | UCSD · Department of Bioengineering

Near-infrared (NIR) radiation has been employed using one-and two-photon excitation of fluorescence imaging at wavelengths 650–950 nm (optical window I) for deep brain imaging; however, longer wavelengths in NIR have been overlooked due to a lack of suitable NIR-low band gap semiconductor imaging detectors and/or femtosecond laser sources. This res...

Direct visualization of metabolic dynamics in living animals with high spatial and temporal resolution is essential to understanding many biological processes. Here we introduce a platform that combines deuterium oxide (D2O) probing with stimulated Raman scattering (DO-SRS) microscopy to image in situ metabolic activities. Enzymatic incorporation o...

Cells and tissues often display pronounced spatial and dynamical metabolic heterogeneity. Common glucose-imaging techniques report glucose uptake or catabolism activity, yet do not trace the functional utilization of glucose-derived anabolic products. Here we report a microscopy technique for the optical imaging, via the spectral tracing of deuteri...

Lipid metabolism plays crucial roles during aging processes, but how it is regulated by diets and how it interplays with aging still remain unclear. We proposed a new optical imaging platform by integrating heavy water (D2O) probing with stimulated Raman scattering (DO‐SRS) microscopy, for the first time, to directly visualize and quantify lipid me...

Stimulated Raman scattering (SRS) offers the ability to image metabolic dynamics with high signal-to-noise ratio. However, its spatial resolution is limited by the numerical aperture of the imaging objective and the scattering cross-section of molecules. To achieve super-resolved SRS imaging, we developed a deconvolution algorithm, adaptive moment...

This work reports on the first use of the Optical Kerr Effect (OKE) in breast cancer tissue. This proposed optical biopsy method utilizes a Femtosecond Optical Kerr Gate to detect changes in dielectric relaxation and conductivity created by a cancerous infection. Here, the temporal behavior of the OKE is tracked in normal and cancerous samples of h...

Triple negative breast cancer (TNBC) is a highly aggressive form of cancer. Detecting TNBC early is crucial for improving disease prognosis and optimizing treatment. Unfortunately, conventional imaging techniques fall short in providing a comprehensive differentiation of TNBC subtypes due to their limited sensitivity and inability to capture subcel...

A new approach for early detection of multiple cancers is presented by integrating SERS spectroscopy of serum molecular fingerprints and machine learning.

Colorimetric biosensors based on gold nanoparticle (AuNP) aggregation are often challenged by matrix interference in biofluids, poor specificity, and limited utility with clinical samples. Here, we propose a peptide-driven nanoscale disassembly approach, where AuNP aggregates induced by electrostatic attractions are dissociated in response to prote...

Studies have shown that brain lipid metabolism is associated with biological aging and influenced by dietary and genetic manipulations; however, the underlying mechanisms are elusive. High-resolution imaging techniques propose a novel and potent approach to understanding lipid metabolic dynamics in situ. Applying deuterium water (D2O) probing with...

The Optical Kerr Effect was demonstrated for the first time as a new optical biopsy method to detect normal and grades of cancer of human breast tissues. The technique works by temporally tracking the various electronic and molecular processes that give rise to the nonlinear index of refraction (n 2 ). The rate at which these processes populate and...

Traumatic brain injury (TBI) can lead to neurodegenerative diseases such as Alzheimer’s disease (AD) through mechanisms that remain incompletely characterized. Similar to AD, TBI models present with cellular metabolic alterations and modulated cleavage of amyloid precursor protein (APP). Specifically, AD and TBI tissues display increases in amyloid...

Lipid metabolism has been associated with brain aging and is regulated by diet, however, the underlying mechanisms are elusive. Using deuterium water (D2O) probed stimulated Raman scattering (SRS) imaging, we demonstrated brain lipid metabolism in Drosophila manipulated by diet in an age- and sex-dependent manner, and important roles of glial insul...

This paper focuses on the study of the transmission of the cerebellum tissue at different oxygen levels and the interaction with multipoles of well-defined polarized orbital angular momentum (OAM) beams, known as optical vortices. The optical vortices interacting with the cerebellum tissue play a key role in our research. The electric field of thes...

The generation, manipulation and quantification of non-classical light, such as quantum-entangled photon pairs, differs significantly from methods with classical light. Thus, quantum measures could be harnessed to give new information about the interaction of light with matter. In this study we investigate if quantum entanglement can be used to dia...

Aging is associated with progressive declines in physiological integrity and functions alongside increases in vulnerability to develop a number of diseases. The brain regulates sensory and motor functions as well as endocrine functions, and age-associated changes in brain are likely prerequisite for the organismal aging. Lipid metabolism has been a...

Lipids play crucial roles in many biological processes under physiological and pathological conditions. Mapping spatial distribution and examining metabolic dynamics of different lipids in cells and tissues in situ are critical for understanding aging and diseases. Commonly used imaging methods, including mass spectrometry-based technologies or lab...

Unlike traditionally-mapped Raman imaging, stimulated Raman scattering (SRS) imaging achieved the capability of imaging metabolic dynamics and a greatly improved signal-noise-ratio. However, its spatial resolution is still limited by the numerical aperture or scattering cross section. To achieve super-resolved SRS imaging, we developed a new deconv...

Calcium signaling in cerebrovascular endothelial cells (CVECs) has been identified to play key physiological and pathological roles in blood brain barrier function and neurovascular coupling, which involve dynamic changes in vessel diameter. However, there are no studies that measured correlated changes in vessel diameter and calcium activity in CV...

Understanding metabolism is of great significance to decipher various physiological and pathogenic processes. While great progress has been made to profile gene expression, how to capture organ‐, tissue‐, and cell‐type‐specific metabolic profile (i.e., metabolic tissue atlas) in complex mammalian systems is lagging behind, largely owing to the lack...

Triple negative breast cancer (TNBC) is a particularly aggressive cancer subtype that is difficult to diagnose due to its discriminating epidemiology and obscure metabolome. For the first time, 3D spatial and chemometric analyses uncover the unique lipid metabolome of TNBC under the tandem modulation of two key metabolites – insulin and methionine...

Mapping the localization of multiple proteins in their native three-dimensional (3D) context would be useful across many areas of biomedicine, but multiplexed fluorescence imaging has limited intrinsic multiplexing capability, and most methods for increasing multiplexity can only be applied to thin samples (<100 µm). Here, we harness the narrow spe...

Microtubules are self-assembling biological nanotubes made of the protein tubulin that are essential for cell motility, cell architecture, cell division and intracellular trafficking. They demonstrate unique mechanical properties of high resilience and stiffness due to their quasi-crystalline helical structure. It has been theorized that this hollo...

The differences in the Raman linewidth of 1086 cm⁻¹ A1g mode were measured for O- and E-waves in calcite crystals. The linewidth for the O-wave was found to be larger than the E-wave phonon excited 1086 cm⁻¹ mode, indicating a faster 1086 cm⁻¹ optical phonon dephasing lifetime T2 for generating O-wave than E-wave modes. The difference in linewidths...

Significance This article demonstrates a high-throughput technique to map cell images to cell positions. The technology uses a three-dimensional (3D) imaging flow cytometer to record multiparameter 3D cell images at a throughput of 1,000 cells/s and a cell placement robot to place the exiting cells from the imaging system on a filter plate in a fir...

Emerging studies have shown that lipids and proteins play versatile roles in various aspects of aging. High-resolution in situ optical imaging provides a powerful approach to study the metabolic dynamics of lipids and proteins during aging. Here, we integrated D 2 O probing and stimulated Raman scattering (DO-SRS) microscopy to directly visualize m...

The stage of development during the mammalian life cycle is dependent on the effects of tryptophan (Trp) and its metabolites. Studies on Trp metabolism utilize a variety of approaches (such as biochemical detection mechanisms of Trp) to show changes in Trp and Trp metabolite levels in different tissues and body fluids. Biophotonics has been recentl...

Deuterium labeling has been widely used for SRS metabolic imaging. It is the minimum label that causes little perturbation to the biochemical property of target molecules. In this chapter, we introduce the applications of deuterium-probed SRS metabolic imaging in living organisms. We first review recent developments of two SRS imaging techniques th...

Oxidative imbalance plays an essential role in the progression of many diseases that include cancer and neurodegenerative diseases. Aromatic amino acids (AAA) such as phenylalanine and tryptophan have the capability of escalating oxidative stress because of their involvement in the production of Reactive Oxygen Species (ROS) . Here, we use D 2 O (h...

Emerging studies have shown that lipid metabolism plays an important role in aging. High resolution in situ imaging of lipid metabolic dynamics inside cells and tissues affords a novel and potent approach for understanding many biological processes such as aging. Here we established a new optical imaging platform that combines D2O-probed stimulated...

Unlike traditionally-mapped Raman imaging, stimulated Raman scattering (SRS) imaging achieved the capability of imaging metabolic dynamics and a greatly improved signal-noise-ratio. However, its spatial resolution is still limited by the numerical aperture or scattering cross-section. To achieve super-resolved SRS imaging, we developed a new deconv...

Extreme spectral broadening has been theoretically simulated from the index of refraction changes from the envelope response to the fifth- and third-order susceptibilities from self-phase modulation (SPM) under the influence of an extremely high-intensity femtosecond laser pulse to potentially produce spectral broadening changes extending from extr...

An electromagnetic model is presented to explain the higher harmonic generation. The electronic cloud distortion model is used based on the carrier-envelope phase at the optical cycle response for gases and solids to explain the experimental Higher Harmonic Generation (HHG) and Supercontinuum Generation from the interaction of high-intensity ultraf...

Defining the relationship between vascular development and the expression of hypoxia-inducible factors (Hifs) and vascular endothelial growth factor (Vegf) in the auditory brainstem is important to understand how tissue hypoxia caused by oxygen shortage contributes to sensory deficits in neonates. In this study, we used histology, molecular labelin...

The blood-brain barrier (BBB) is a unique interface between the cerebral circulation and the brain. It plays crucial roles in facilitating the brain nutrient uptake and waste removal, maintaining the stability of the micro-environment in the central nervous system (CNS), and protecting the CNS under physiological and pathological conditions. On the...

A classical electrodynamics theoretical model is presented to explain the Odd Higher Harmonic Generation (HHG) from the electronic response n2 SPM effects in rare gases and condensed matter in contrast to the quantum mechanical model.

Traumatic brain injury (TBI) is a major cause of death and disability in the United States. A history of TBI can lead to neurodegenerative diseases such as Alzheimer's disease (AD) in a severity-and frequency-dependent manner. We previously reported that early stages of AD are characterized by alterations in lipid metabolism due to upregulated func...

Stimulated Raman scattering (SRS) microscopy has emerged in the last decade as a powerful optical imaging technology with high chemical selectivity, speed, and subcellular resolution. Since the invention of SRS microscopy, it has been extensively employed in life science to study composition, structure, metabolism, development, and disease in biolo...

Understanding metabolism is indispensable in unraveling the mechanistic basis of many physiological and pathological processes. However, in situ metabolic imaging tools are still lacking. Here we introduce a framework for mid-infrared (MIR) metabolic imaging by coupling the emerging high-information-throughput MIR microscopy with specifically desig...

Direct imaging of metabolism in cells or multicellular organisms is important for understanding many biological processes. Raman scattering (RS) microscopy, particularly, coherent Raman scattering (CRS) such as coherent anti‐Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS), has emerged as a powerful platform for cellular imaging...

A special, newly proposed photon called a "Majorana-like" photon possesses spin angular momentum (SAM) and orbit angular momentum (OAM) coupled together. Experiments with mouse brain tissue have revealed the plausibility of using these special photons in imaging and communications applications and possibly in optical quantum computing applications...

A new nonlinear optical process, named enhanced stimulated Raman scattering (ESRS), is reported for the first time from resonance Raman in β-carotene-methanol solution. It is well known that absorption decreases the efficiency of the nonlinear optical and laser processes; however, we observed enhanced stimulated Raman peaks at the first and second...

Key optical properties of calcite were measured to unravel the difference between stimulated Raman scattering (SRS) and self-phase modulation (SPM) for the supercontinuum (SC) for ordinary (O) wave and extraordinary (E) wave. These properties are group velocity dispersion, walk-off, spontaneous Raman spectra and cross section, optical 1086cm-1 phon...

Being able to image chemical bonds with high sensitivity and speed, stimulated Raman scattering (SRS) microscopy has made a major impact in biomedical optics. However, it is well known that the standard SRS microscopy suffers from various backgrounds, limiting the achievable contrast, quantification and sensitivity. While many frequency-modulation...

Triple‐negative breast cancer (TNBC) is an aggressive subset of breast cancer that is more common in African‐American and Hispanic women. Early detection followed by intensive treatment is critical to improving poor survival rates. The current standard to diagnose TNBC from histopathology of biopsy samples is invasive and time‐consuming. Imaging me...