Modeling and Predicting Second-Harmonic Generation from Protein Molecular Structure

Cancer Research

Mismatch repair deficient (MMRd) status is a predictive biomarker for Immune checkpoint inhibitors (ICI) in endometrial cancer (EC), however, half of these patients (pts) do not respond. Most studies exploring biomarkers of response to ICI have focused on tumor or immune cell factors. We aimed to describe the extracellular matrix components of the tumor microenvironment (TME) in ICI-Responder (R) versus Non-Responder (NR) MMRd EC pts to identify new predictive biomarkers of response. Clinical data and outcomes of metastatic MMRd EC pts, treated with ICI (2016-2021), were retrospectively collected. Pts were classified as Rs (CR, PR, or SD ≥12 months) or NRs (PD or SD <12 months). Pre-ICI FFPE tumor samples were subjected to Biognosys UltraDeep TrueDiscovery™ Mass Spectrometry (MS) for identification of differentially regulated protein expression between R and NR. Criteria for protein candidate …

Biophysical Journal

Fluorescence lifetime imaging microscopy (FLIM) is a powerful technique used to probe the local environment of fluorophores. The fit-free phasor approach to FLIM data is increasingly being used due to its ease of interpretation. To date, no open-source graphical user interface (GUI) for phasor analysis of FLIM data is available in Python, thus limiting the widespread use of phasor analysis in biomedical research. Here we present (F) luorescence (L) ifetime (U) l (t) imate (E) xplorer (FLUTE), the first open-source graphical user interface (GUI) for phasor analysis of FLIM data programmed in Python, one of the most widely used programming languages. FLUTE is free to use under the BSD-3-Clause license, and can be found at: https://github. com/LaboratoryOpticsBiosciences/FLUTE. Both the code to be executed in Python and a packaged. exe, which requires no installation, are available. FLUTE simplifies and …

iScience

Spatial genome organization within the nucleus influences major biological processes and is impacted by the configuration of linear chromosomes. Here, we applied 3D spatial statistics and modeling on high resolution telomere and centromere 3D-SIM images in cancer cells. We found a multi-scale organization of telomeres that dynamically evolved from a mixed clustered-and-regular distribution in early G1 to a purely regular distribution as cells progressed through the cell cycle. In parallel, our analysis revealed two pools of peripheral and internal telomeres, the proportions of which were inverted during the cell cycle. We then conducted a targeted screen using MadID to identify the molecular pathways driving or maintaining telomere anchoring to the nuclear envelope observed in early G1. LAP proteins were found transiently localized to telomeres in anaphase, a stage where LAP2α initiates the reformation of …

bioRxiv

BiaPy, a unified open-source bioimage analysis library, offers a comprehensive suite of deep learning-powered workflows. Tailored for users of all levels, BiaPy features an intuitive interface, zero-code notebooks, and Docker integration. With support for 2D and 3D image data, it addresses existing gaps by providing multi-GPU capabilities, memory optimization, and compatibility with large datasets. As a collaborative and accessible solution, BiaPy aims to empower researchers by democratizing the use of sophisticated and efficient bioimage analysis workflows.

Wide-field Imaging Mueller polarimetry (IMP) is capable to trace the in-plane orientation of brain fiber tracts by detecting the retardance of healthy brain white matter. IMP can help delineating brain tumor during neurosurgery, because tumor cells grow chaotically. However, the underlying crossing fibers may also affect the retardance of healthy brain. We measured with the transmission Mueller microscope two-layered stacks of thin sections of brain corpus callosum tissue. Brain fiber crossing induced the drop in the linear retardance values and azimuth randomization. The depolarization was invariant to mutual orientation of corpus callosum stripes, hence, the studies of brain tumor depolarization may help to distinguish brain tumor from the fiber crossing zones.

Biophysical Journal

Wednesday, February 14, 2024 555a mimicking immune synapse formation. 2P-FLIM measurements of the protein-bound and free NAD (P) H ratios provide a readout of the redox state (NADþ/NAD (P) H of the cells, and thus of their OXPHOS and glycolysis rates. Using this method, we followed the dynamics of fraction of bound NAD (P) H in live single cells. Comparing the fraction of bound NAD (P) H between resting and activated T cells, we show, in both T cell models, that T cell activation induces a rapid switch toward glycolysis. This switch occurs after 10 minutes and remains stable for at least one hour. Three-dimensional (3D) analyzes revealed that the intracellular distribution of fraction of bound NAD (P) H increases at the surrogate immune synapse in activated cells. Finally, we show that fraction of bound NAD (P) H tends to negatively correlate with spreading of activated T cells, suggesting a link between …

Biophysical Journal

One central question in neuroscience and multiple sclerosis (MS) is how the metabolic coupling between microglia, oligodendrocytes (OLs) and neurons modulate myelin formation, demyelination, remyelination as well as neuronal energetic status and supply failure. The metabolic interplay between different cells has not been studied before at the single-cell level because of the lack of appropriate microscopy techniques. Here we develop advanced multimodal label-free and non-invasive techniques based on non-linear optics and intrinsic biomarkers to image myelin and metabolism with subcellular resolution. We implemented third-harmonic generation (THG) microscopy to probe myelin organization with single fiber resolution and two-photon excitation fluorescence lifetime microscopy (2P-FLIM) of the metabolic biomarkers NAD (P) H and FAD for measurements of cellular redox states and glycolysis and …

bioRxiv

The archaeal domain is a taxonomically rich component of microbial communities that inhabit a wide range of habitats on Earth, including the human body. Phylogenomic analyses have indicated that archaea represent the closest known relatives of eukaryotes, thus suggesting that eukaryotes may have evolved from an archaeal ancestor. G-quadruplex structures (G4), formed by guanine rich sequences, are among the most intensively studied local DNA/RNA structures and regulate key biological processes such as replication and gene expression. A bioinformatics analysis of the genome of the salt-loving archaea H. volcanii revealed a large number of potential G4 sequences (PQS). Biophysical analyses showed that a representative panel of these sequences form stable G4 structures under physiological conditions in vitro. In addition, immunofluorescence experiments using the G4-specific antibody, BG4, detected G4s in vivo at the single-cell level with super-resolution microscopy. Moreover, we directly visualized G4 in exponentially growing or stationary cells both at the DNA and RNA levels. G4s were also observed in the RNA and DNA of the hyperthermophile archaeon T. barophilus. Finally, we identified helicases potentially involved in G4 unfolding. Together, with H. volcanii as a new model, our work helps to fill the gap between bacteria and eukaryotic organisms for G4 studies and will aid in uncovering the evolutionary history of G4 structures in the tree of life.

Developmental Cell

Congenital heart malformations include mitral valve defects, which remain largely unexplained. During embryogenesis, a restricted population of endocardial cells within the atrioventricular canal undergoes an endothelial-to-mesenchymal transition to give rise to mitral valvular cells. However, the identity and fate decisions of these progenitors as well as the behavior and distribution of their derivatives in valve leaflets remain unknown. We used single-cell RNA sequencing (scRNA-seq) of genetically labeled endocardial cells and microdissected mouse embryonic and postnatal mitral valves to characterize the developmental road. We defined the metabolic processes underlying the specification of the progenitors and their contributions to subtypes of valvular cells. Using retrospective multicolor clonal analysis, we describe specific modes of growth and behavior of endocardial cell-derived clones, which build up, in a …

Stem cells possess extraordinary capacities for self-renewal and differentiation, making them highly valuable in regenerative medicine. Among these, neural stem cells (NSCs) play a fundamental role in neural development and repair processes. NSC characteristics and fate are intricately regulated by the microenvironment and intracellular signaling. Interestingly, metabolism plays a pivotal role in orchestrating the epigenome dynamics during neural differentiation, facilitating the transition from undifferentiated NSC to specialized neuronal and glial cell types. This intricate interplay between metabolism and the epigenome is essential for precisely regulating gene expression patterns and ensuring proper neural development. This review highlights the mechanisms behind metabolic regulation of NSC fate and their connections with epigenetic regulation to shape transcriptional programs of stemness and neural …

Biophysical Journal

One central question in neuroscience and multiple sclerosis (MS) is how the metabolic coupling between microglia, oligodendrocytes (OLs) and neurons modulate myelin formation, demyelination, remyelination as well as neuronal energetic status and supply failure. The metabolic interplay between different cells has not been studied before at the single-cell level because of the lack of appropriate microscopy techniques. Here we develop advanced multimodal label-free and non-invasive techniques based on non-linear optics and intrinsic biomarkers to image myelin and metabolism with subcellular resolution. We implemented third-harmonic generation (THG) microscopy to probe myelin organization with single fiber resolution and two-photon excitation fluorescence lifetime microscopy (2P-FLIM) of the metabolic biomarkers NAD (P) H and FAD for measurements of cellular redox states and glycolysis and …

iScience

Spatial genome organization within the nucleus influences major biological processes and is impacted by the configuration of linear chromosomes. Here, we applied 3D spatial statistics and modeling on high resolution telomere and centromere 3D-SIM images in cancer cells. We found a multi-scale organization of telomeres that dynamically evolved from a mixed clustered-and-regular distribution in early G1 to a purely regular distribution as cells progressed through the cell cycle. In parallel, our analysis revealed two pools of peripheral and internal telomeres, the proportions of which were inverted during the cell cycle. We then conducted a targeted screen using MadID to identify the molecular pathways driving or maintaining telomere anchoring to the nuclear envelope observed in early G1. LAP proteins were found transiently localized to telomeres in anaphase, a stage where LAP2α initiates the reformation of …

Biophysical Journal

One central question in neuroscience and multiple sclerosis (MS) is how the metabolic coupling between microglia, oligodendrocytes (OLs) and neurons modulate myelin formation, demyelination, remyelination as well as neuronal energetic status and supply failure. The metabolic interplay between different cells has not been studied before at the single-cell level because of the lack of appropriate microscopy techniques. Here we develop advanced multimodal label-free and non-invasive techniques based on non-linear optics and intrinsic biomarkers to image myelin and metabolism with subcellular resolution. We implemented third-harmonic generation (THG) microscopy to probe myelin organization with single fiber resolution and two-photon excitation fluorescence lifetime microscopy (2P-FLIM) of the metabolic biomarkers NAD (P) H and FAD for measurements of cellular redox states and glycolysis and …

Physical Review X

The deconfined quark-gluon plasma (QGP) created in relativistic heavy-ion collisions enables the exploration of the fundamental properties of matter under extreme conditions. Noncentral collisions can produce strong magnetic fields on the order of 10 18 G, which offers a probe into the electrical conductivity of the QGP. In particular, quarks and antiquarks carry opposite charges and receive contrary electromagnetic forces that alter their momenta. This phenomenon can be manifested in the collective motion of final-state particles, specifically in the rapidity-odd directed flow, denoted as v 1 (y). Here, we present the charge-dependent measurements of d v 1/d y near midrapidities for π±, K±, and p (p) in Au+ Au and isobar (Ru 44 96+ Ru 44 96 and Zr 40 96+ Zr 40 96) collisions at s NN= 200 GeV, and in Au+ Au collisions at 27 GeV, recorded by the STAR detector at the Relativistic Heavy Ion Collider. The combined …

Physical Review X

Polarization resolved second-harmonic-generation (pSHG) microscopy is increasingly used for mapping organized arrays of non-centrosymmetric proteins such as collagen, myosin and tubulin, and holds potential for probing their molecular structure and supramolecular organization in intact tissues. However, the contrast mechanism of pSHG is complex, and the development of applications in the life sciences is hampered by the lack of models accurately relating the observed pSHG signals to the underlying molecular and macromolecular organization. In this work, we establish a general multi-scale numerical framework relating the micrometer-scale SHG measurements to the atomic-scale and molecular structure of the proteins under study and their supramolecular arrangement. We first develop a new method to automatically analyze pSHG signals independently of the protein type and fiber orientation. We then …

Physical Review X

The deconfined quark-gluon plasma (QGP) created in relativistic heavy-ion collisions enables the exploration of the fundamental properties of matter under extreme conditions. Noncentral collisions can produce strong magnetic fields on the order of 10 18 G, which offers a probe into the electrical conductivity of the QGP. In particular, quarks and antiquarks carry opposite charges and receive contrary electromagnetic forces that alter their momenta. This phenomenon can be manifested in the collective motion of final-state particles, specifically in the rapidity-odd directed flow, denoted as v 1 (y). Here, we present the charge-dependent measurements of d v 1/d y near midrapidities for π±, K±, and p (p) in Au+ Au and isobar (Ru 44 96+ Ru 44 96 and Zr 40 96+ Zr 40 96) collisions at s NN= 200 GeV, and in Au+ Au collisions at 27 GeV, recorded by the STAR detector at the Relativistic Heavy Ion Collider. The combined …

Physical Review X

Quantum simulators built from ultracold atoms promise to study quantum phenomena in interacting many-body systems. However, it remains a challenge to experimentally prepare strongly correlated continuous systems such that the properties are dominated by quantum fluctuations. Here, we show how to enhance the quantum correlations in a one-dimensional multimode bosonic Josephson junction, which is a quantum simulator of the sine-Gordon field theory. Our approach is based on the ability to track the nonequilibrium dynamics of quantum properties. After creating a bosonic Josephson junction at the stable fixed point of the classical phase space, we observe squeezing oscillations in the two conjugate variables. We show that the squeezing oscillation frequency can be tuned by more than one order of magnitude, and we are able to achieve a spin squeezing close to 10 dB by utilizing these oscillatory …

Physical Review X

Optical nonreciprocity plays a key role in almost every optical system, directing light flow and protecting optical components from backscattered light. Controllable forms of on-chip nonreciprocity are needed for the robust operation of increasingly sophisticated photonic integrated circuits (PICs) in the context of classical and quantum computation, networking, communications, and sensing. However, it has been challenging to achieve wideband, low-loss optical nonreciprocity on-chip. In this paper, we demonstrate strong coupling and Rabi-like energy exchange between photonic bands, possessing a continuum of modes, to unlock nonreciprocity and frequency translation over wide optical bandwidths in silicon. Using a traveling-wave phonon field to drive indirect interband photonic transitions, we demonstrate band hybridization that enables an intriguing form of nonreciprocal dissipation engineering. Using the …

Physical Review X

We generalize the notion of quantum state designs to infinite-dimensional spaces. We first prove that, under the definition of continuous-variable (CV) state t-designs from [Blume-Kohout et al., Commun. Math. Phys. 326, 755 (2014)], no state designs exist for t≥ 2. Similarly, we prove that no CV unitary t-designs exist for t≥ 2. We propose an alternative definition for CV state designs, which we call rigged t-designs, and provide explicit constructions for t= 2. As an application of rigged designs, we develop a design-based shadow-tomography protocol for CV states. Using energy-constrained versions of rigged designs, we define an average fidelity for CV quantum channels and relate this fidelity to the CV entanglement fidelity. As an additional result of independent interest, we establish a connection between torus 2-designs and complete sets of mutually unbiased bases.

Physical Review X

Many organisms exhibit branching morphologies that twist around each other and become entangled. Entanglement occurs when different objects interlock with each other, creating complex and often irreversible configurations. This physical phenomenon is well studied in nonliving materials, such as granular matter, polymers, and wires, where it has been shown that entanglement is highly sensitive to the geometry of the component parts. However, entanglement is not yet well understood in living systems, despite its presence in many organisms. In fact, recent work has shown that entanglement can evolve rapidly and play a crucial role in the evolution of tough, macroscopic multicellular groups. Here, through a combination of experiments, simulations, and numerical analyses, we show that growth generically facilitates entanglement for a broad range of geometries. We find that experimentally grown entangled …

Physical Review X

Optical nonreciprocity plays a key role in almost every optical system, directing light flow and protecting optical components from backscattered light. Controllable forms of on-chip nonreciprocity are needed for the robust operation of increasingly sophisticated photonic integrated circuits (PICs) in the context of classical and quantum computation, networking, communications, and sensing. However, it has been challenging to achieve wideband, low-loss optical nonreciprocity on-chip. In this paper, we demonstrate strong coupling and Rabi-like energy exchange between photonic bands, possessing a continuum of modes, to unlock nonreciprocity and frequency translation over wide optical bandwidths in silicon. Using a traveling-wave phonon field to drive indirect interband photonic transitions, we demonstrate band hybridization that enables an intriguing form of nonreciprocal dissipation engineering. Using the …

Physical Review X

The ultrafast manipulation of quantum material has led to many novel and significant discoveries. Among them, the light-induced transient superconductivity in cuprates achieved by melting competing stripe orders represents a highly appealing accomplishment. However, recent investigations have shown that the notion of photoinduced superconductivity remains a topic of controversy, and its elucidation solely through c-axis time-resolved terahertz spectroscopy remains an arduous task. Here, we measure the in-plane and out-of-plane transient terahertz responses simultaneously in the stripe-ordered nonsuperconducting La 2− x Ba x CuO 4 after near-infrared excitations. We find that although a pump-induced reflectivity edge appears in the c-axis reflectance spectrum, the reflectivity along the CuO 2 planes decreases simultaneously, indicating an enhancement in the scattering rate of quasiparticles. This in-plane …

Physical Review X

Coupled cluster theory is one of the most popular post-Hartree-Fock methods for ab initio molecular quantum chemistry. The finite-size error of the correlation energy in periodic coupled cluster calculations for three-dimensional insulating systems has been observed to satisfy the inverse volume scaling, even in the absence of any correction schemes. This is surprising, as simpler theories that utilize only a subset of the coupled cluster diagrams exhibit much slower decay of the finite-size error, which scales inversely with the length of the system. In this study, we review the current understanding of finite-size error in quantum chemistry methods for periodic systems. We introduce new tools that elucidate the mechanisms behind this phenomenon in the context of coupled cluster doubles calculations. This reconciles some seemingly paradoxical statements related to finite-size scaling. Our findings also show that …

Physical Review X

Spontaneous symmetry breaking—the phenomenon in which an infinitesimal perturbation can cause the system to break the underlying symmetry—is a cornerstone concept in the understanding of interacting solid-state systems. In a typical series of temperature-driven phase transitions, higher-temperature phases are more symmetric due to the stabilizing effect of entropy that becomes dominant as the temperature is increased. However, the opposite is rare but possible when there are multiple degrees of freedom in the system. Here, we present such an example of a symmetry-ascending phenomenon upon cooling in a magnetic kagome metal FeGe by utilizing neutron Larmor diffraction and Raman spectroscopy. FeGe has a kagome lattice structure with simple A-type antiferromagnetic order below Néel temperature T N≈ 400 K and a charge density wave (CDW) transition at T CDW≈ 110 K, followed by a spin …

Physical Review X

The deconfined quark-gluon plasma (QGP) created in relativistic heavy-ion collisions enables the exploration of the fundamental properties of matter under extreme conditions. Noncentral collisions can produce strong magnetic fields on the order of 10 18 G, which offers a probe into the electrical conductivity of the QGP. In particular, quarks and antiquarks carry opposite charges and receive contrary electromagnetic forces that alter their momenta. This phenomenon can be manifested in the collective motion of final-state particles, specifically in the rapidity-odd directed flow, denoted as v 1 (y). Here, we present the charge-dependent measurements of d v 1/d y near midrapidities for π±, K±, and p (p) in Au+ Au and isobar (Ru 44 96+ Ru 44 96 and Zr 40 96+ Zr 40 96) collisions at s NN= 200 GeV, and in Au+ Au collisions at 27 GeV, recorded by the STAR detector at the Relativistic Heavy Ion Collider. The combined …

Physical Review X

Active constituents burn fuel to sustain individual motion, giving rise to collective effects that are not seen in systems at thermal equilibrium, such as phase separation with purely repulsive interactions. There is a great potential in harnessing the striking phenomenology of active matter to build novel controllable and responsive materials that surpass passive ones. Yet, we currently lack a systematic roadmap to predict the protocols driving active systems between different states in a way that is thermodynamically optimal. Equilibrium thermodynamics is an inadequate foundation to this end, due to the dissipation rate arising from the constant fuel consumption in active matter. Here, we derive and implement a versatile framework for the thermodynamic control of active matter. Combining recent developments in stochastic thermodynamics and response theory, our approach shows how to find the optimal control for …

Physical Review X

The discrepancies between reality and simulation impede the optimization and scalability of solid-state quantum devices. Disorder induced by the unpredictable distribution of material defects is one of the major contributions to the reality gap. We bridge this gap using physics-aware machine learning, in particular, using an approach combining a physical model, deep learning, Gaussian random field, and Bayesian inference. This approach enables us to infer the disorder potential of a nanoscale electronic device from electron-transport data. This inference is validated by verifying the algorithm’s predictions about the gate-voltage values required for a laterally defined quantum-dot device in AlGaAs/GaAs to produce current features corresponding to a double-quantum-dot regime.

Physical Review X

B22. 00004: Defect-induced low-energy Majorana excitations in the Kitaev magnet α-RuCl 3

Physical Review X

Many organisms exhibit branching morphologies that twist around each other and become entangled. Entanglement occurs when different objects interlock with each other, creating complex and often irreversible configurations. This physical phenomenon is well studied in nonliving materials, such as granular matter, polymers, and wires, where it has been shown that entanglement is highly sensitive to the geometry of the component parts. However, entanglement is not yet well understood in living systems, despite its presence in many organisms. In fact, recent work has shown that entanglement can evolve rapidly and play a crucial role in the evolution of tough, macroscopic multicellular groups. Here, through a combination of experiments, simulations, and numerical analyses, we show that growth generically facilitates entanglement for a broad range of geometries. We find that experimentally grown entangled …

Physical Review X

The asymmetric distribution of chiral objects with opposite chirality is of great fundamental interest ranging from molecular biology to particle physics. In quantum materials, chiral states can build on inversion-symmetry-breaking lattice structures or emerge from spontaneous magnetic ordering induced by competing interactions. Although the handedness of a chiral state can be changed through external fields, a spontaneous chirality flipping has yet to be discovered. We present experimental evidence of chirality flipping via changing temperature in a topological magnet EuAl 4, which features orthogonal spin density waves (SDW) and charge density waves (CDW). Using circular dichroism of Bragg peaks in the resonant magnetic x-ray scattering, we find that the chirality of the helical SDW flips through a first-order phase transition with modified SDW wavelength. Intriguingly, we observe that the CDW couples strongly …

Physical Review X

The motion of electrons in the vast majority of conductors is diffusive, obeying Ohm’s law. However, the recent discovery and growth of high-purity materials with extremely long electronic mean free paths has sparked interest in non-Ohmic alternatives, including viscous and ballistic flow. Although non-Ohmic transport regimes have been discovered across a range of materials—including two-dimensional electron gases, graphene, topological semimetals, and the delafossite metals—determining their nature has proved to be challenging. Here, we report on a new approach to the problem, employing broadband microwave spectroscopy of the delafossite metal PdCoO 2 in three distinct sample geometries that would be identical for diffusive transport. The observed differences, which go as far as differing power laws, take advantage of the hexagonal symmetry of the conducting Pd planes of PdCoO 2. This permits a …

Physical Review X

Electrostrictive Brillouin scattering provides a ubiquitous mechanism to optically excite high-frequency (> 10 GHz), bulk acoustic phonons that are robust to surface-induced losses. Resonantly enhancing such photon-phonon interactions in high-Q microresonators has spawned diverse applications spanning microwave to optical domains. However, tuning both the pump and scattered waves into resonance usually comes with the cost of photon confinement or modal overlap, leading to limited optomechanical coupling. Here, we introduce Bragg scattering to realize strong bulk optomechanical coupling in the same spatial modes of a micron-sized supermode microresonator. A single-photon optomechanical coupling rate up to 12.5 kHz is demonstrated, showing more than 10 times improvement than other devices. Low-threshold phonon lasing and optomechanical strong coupling are also observed for the 10.2-GHz …

Physical Review X

Optical nonreciprocity plays a key role in almost every optical system, directing light flow and protecting optical components from backscattered light. Controllable forms of on-chip nonreciprocity are needed for the robust operation of increasingly sophisticated photonic integrated circuits (PICs) in the context of classical and quantum computation, networking, communications, and sensing. However, it has been challenging to achieve wideband, low-loss optical nonreciprocity on-chip. In this paper, we demonstrate strong coupling and Rabi-like energy exchange between photonic bands, possessing a continuum of modes, to unlock nonreciprocity and frequency translation over wide optical bandwidths in silicon. Using a traveling-wave phonon field to drive indirect interband photonic transitions, we demonstrate band hybridization that enables an intriguing form of nonreciprocal dissipation engineering. Using the …