Person: Xie, Xiaoliang
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Xiaoliang
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Xie, Xiaoliang
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Publication Video Rate Molecular Imaging In Vivo with Stimulated Raman Scattering(American Association for the Advancement of Science, 2010) Saar, Brian; Freudiger, Christian Wilhelm; Reichman, Jay; Stanley, C. Michael; Holtom, Gary; Xie, XiaoliangOptical imaging in vivo with molecular specificity is important in biomedicine because of its high spatial resolution and sensitivity compared with magnetic resonance imaging. Stimulated Raman scattering (SRS) microscopy allows highly sensitive optical imaging based on vibrational spectroscopy without adding toxic or perturbative labels. However, SRS imaging in living animals and humans has not been feasible because light cannot be collected through thick tissues, and motion-blur arises from slow imaging based on backscattered light. In this work, we enable in vivo SRS imaging by substantially enhancing the collection of the backscattered signal and increasing the imaging speed by three orders of magnitude to video rate. This approach allows label-free in vivo imaging of water, lipid, and protein in skin and mapping of penetration pathways of topically applied drugs in mice and humans.Publication Multicolor Stimulated Raman Scattering Microscopy with a Rapidly Tunable Optical Parametric Oscillator(Optical Society of America, 2013) Kong, Lingjie; Ji, Minbiao; Holtom, Gary R.; Fu, Dan; Freudiger, Christian Wilhelm; Xie, XiaoliangStimulated Raman scattering (SRS) microscopy allows label-free chemical imaging based on vibrational spectroscopy. Narrowband excitation with picosecond lasers creates the highest signal levels and enables imaging speeds up to video-rate, but it sacrifices chemical specificity in samples with overlapping bands compared to broadband (multiplex) excitation. We develop a rapidly tunable picosecond optical parametric oscillator with an electro-optical tunable Lyot filter, and demonstrate multicolor SRS microscopy with synchronized line-by-line wavelength tuning to avoid spectral artifacts due to sample movement. We show sensitive imaging of three different kinds of polymer beads and live HeLa cells with moving intracellular lipid droplets.Publication Mapping DNA polymerase errors by single-molecule sequencing(Oxford University Press, 2016) Lee, David; Lu, Jenny; Chang, Seungwoo; Loparo, Joseph; Xie, XiaoliangGenomic integrity is compromised by DNA polymerase replication errors, which occur in a sequence-dependent manner across the genome. Accurate and complete quantification of a DNA polymerase's error spectrum is challenging because errors are rare and difficult to detect. We report a high-throughput sequencing assay to map in vitro DNA replication errors at the single-molecule level. Unlike previous methods, our assay is able to rapidly detect a large number of polymerase errors at base resolution over any template substrate without quantification bias. To overcome the high error rate of high-throughput sequencing, our assay uses a barcoding strategy in which each replication product is tagged with a unique nucleotide sequence before amplification. This allows multiple sequencing reads of the same product to be compared so that sequencing errors can be found and removed. We demonstrate the ability of our assay to characterize the average error rate, error hotspots and lesion bypass fidelity of several DNA polymerases.Publication Relatively slow stochastic gene-state switching in the presence of positive feedback significantly broadens the region of bimodality through stabilizing the uninduced phenotypic state(Public Library of Science, 2018) Ge, Hao; Wu, Pingping; Qian, Hong; Xie, XiaoliangWithin an isogenic population, even in the same extracellular environment, individual cells can exhibit various phenotypic states. The exact role of stochastic gene-state switching regulating the transition among these phenotypic states in a single cell is not fully understood, especially in the presence of positive feedback. Recent high-precision single-cell measurements showed that, at least in bacteria, switching in gene states is slow relative to the typical rates of active transcription and translation. Hence using the lac operon as an archetype, in such a region of operon-state switching, we present a fluctuating-rate model for this classical gene regulation module, incorporating the more realistic operon-state switching mechanism that was recently elucidated. We found that the positive feedback mechanism induces bistability (referred to as deterministic bistability), and that the parameter range for its occurrence is significantly broadened by stochastic operon-state switching. We further show that in the absence of positive feedback, operon-state switching must be extremely slow to trigger bistability by itself. However, in the presence of positive feedback, which stabilizes the induced state, the relatively slow operon-state switching kinetics within the physiological region are sufficient to stabilize the uninduced state, together generating a broadened parameter region of bistability (referred to as stochastic bistability). We illustrate the opposite phenotype-transition rate dependence upon the operon-state switching rates in the two types of bistability, with the aid of a recently proposed rate formula for fluctuating-rate models. The rate formula also predicts a maximal transition rate in the intermediate region of operon-state switching, which is validated by numerical simulations in our model. Overall, our findings suggest a biological function of transcriptional “variations” among genetically identical cells, for the emergence of bistability and transition between phenotypic states.Publication Rare event of histone demethylation can initiate singular gene expression of olfactory receptors(Proceedings of the National Academy of Sciences, 2013) Tan, Longzhi; Zong, Chenghang; Xie, XiaoliangIn mammals, the sense of odors relies on the peculiar expression pattern of olfactory receptors (ORs). Each single neuron chooses one, and only one, from all ∼1,400 OR genes that are present in a mouse genome. In neurobiology, a long-standing mystery is how such singularity can be achieved. We show theoretically that a simple kinetic scheme of OR activation followed by feedback can be solely responsible for the observed singularity, as long as the two timescales—slow activation by epigenetic modification and fast feedback by transcriptional regulation—are well separated. Our work provides the theoretical underpinning behind the choice of ORs, and demonstrates how the nervous system utilizes the kinetics of epigenetic changes to direct neurogenesis.Publication Stimulated Raman Scattering Microscopy with a Robust Fibre Laser Source(Nature Publishing Group, 2014) Freudiger, Christian Wilhelm; Yang, Wenlong; Holtom, Gary; Peyghambarian, Nasser; Xie, Xiaoliang; Kieu, Khanh Q.Stimulated Raman scattering microscopy allows label-free chemical imaging and has enabled exciting applications in biology, material science and medicine. It provides a major advantage in imaging speed over spontaneous Raman scattering and has improved image contrast and spectral fidelity compared to coherent anti-Stokes Raman scattering. Wider adoption of the technique has, however, been hindered by the need for a costly and environmentally sensitive tunable ultrafast dual-wavelength source. We present the development of an optimized all-fibre laser system based on the optical synchronization of two picosecond power amplifiers. To circumvent the high-frequency laser noise intrinsic to amplified fibre lasers, we have further developed a high-speed noise cancellation system based on voltage-subtraction autobalanced detection. We demonstrate uncompromised imaging performance of our fibre-laser-based stimulated Raman scattering microscope with shot-noise-limited sensitivity and an imaging speed up to 1 frame \(s^{−1}\).Publication Quantitative Chemical Imaging with Multiplex Stimulated Raman Scattering Microscopy(American Chemical Society, 2012) Fu, Dan; Lu, Fake; Zhang, Xu; Freudiger, Christian Wilhelm; Pernik, Douglas R.; Holtom, Gary; Xie, XiaoliangStimulated Raman scattering (SRS) microscopy is a newly developed label-free chemical imaging technique that overcomes the speed limitation of confocal Raman microscopy while avoiding the nonresonant background problem of coherent anti-Stokes Raman scattering (CARS) microscopy. Previous demonstrations have been limited to single Raman band measurements. We present a novel modulation multiplexing approach that allows real-time detection of multiple species using the fast Fourier transform. We demonstrate the quantitative determination of chemical concentrations in a ternary mixture. Furthermore, two imaging applications are pursued: (1) quantitative determination of oil content as well as pigment and protein concentration in microalgae cultures; and (2) 3D high-resolution imaging of blood, lipids, and protein distribution in ex vivo mouse skin tissue. We believe that quantitative multiplex SRS uniquely combines the advantage of fast label-free imaging with the fingerprinting capability of Raman spectroscopy and enables numerous applications in lipid biology as well as biomedical imaging.Publication Coherent Anti-Stokes Raman Scattering Microscopy: Chemical Imaging for Biology and Medicine(Annual Reviews, 2008) Evans, Conor; Xie, XiaoliangCoherent anti-Stokes Raman scattering (CARS) microscopy is a label-free imaging technique that is capable of real-time, nonperturbative examination of living cells and organisms based on molecular vibrational spectroscopy. Recent advances in detection schemes, understanding of contrast mechanisms, and developments of laser sources have enabled superb sensitivity and high time resolution. Emerging applications, such as metabolite and drug imaging and tumor identification, raise many exciting new possibilities for biology and medicine.Publication Organelle Tracking in a Living Cell with Microsecond Time Resolution and Nanometer Spatial Precision(Wiley-Blackwell, 2008) Nan, Xiaolin; Sims, Peter Alan; Xie, XiaoliangPublication Two-Dimensional Reaction Free Energy Surfaces of Catalytic Reaction: Effects of Protein Conformational Dynamics on Enzyme Catalysis(American Chemical Society (ACS), 2008) Min, Wei; Xie, Xiaoliang; Bagchi, BimanWe introduce a two-dimensional (2D) multisurface reaction free energy description of the catalytic cycle that explicitly connects the recently observed multi-time-scale conformational dynamics as well as dispersed enzymatic kinetics to the classical Michaelis-Menten equation. A slow conformational motion on a collective enzyme coordinate Q facilitates the catalytic reaction along the intrinsic reaction coordinate X, providing a dynamic realization of Pauling’s well-known idea of transition-state stabilization. The catalytic cycle is modeled as transitions between multiple displaced harmonic wells in the XQ space representing different states of the cycle, which is constructed according to the free energy driving force of the cycle. Subsequent to substrate association with the enzyme, the enzyme-substrate complex under strain exhibits a nonequilibrium relaxation toward a new conformation that lowers the activation energy of the reaction, as first proposed by Haldane. The chemical reaction in X is thus enslaved to the down hill slow motion on the Q surface. One consequence of the present theory is that, in spite of the existence of dispersive kinetics, the Michaelis-Menten expression of the catalysis rate remains valid under certain conditions, as observed in recent single-molecule experiments. This dynamic theory builds the relationship between the protein conformational dynamics and the enzymatic reaction kinetics and offers a unified description of enzyme fluctuation-assisted catalysis.