Biological Physics

Consolidating transient sensory experiences into long-lasting memories is a fundamental function of the brain, linked to synaptic plasticity. The importance of sleep for promoting this process, and the disruptive effect of sleep deprivation on it, have been appreciated for nearly a century. However, it remains unclear how sleep-associated changes in the activity of specific brain circuits contribute to sensory plasticity. Using a combination of longitudinal recordings of neuronal activity in freely-behaving mice, recently-developed optogenetic strategies, novel computational tools for characterizing network activity patterns, we will test the necessity and sufficiency of sleep-associated patterns of thalamocortical activity in consolidating a simple form of experience dependent plasticity. We will test the hypothesis that coherent firing during network oscillations unique NREM sleep plays a causal role in promoting plasticity between the thalamic lateral geniculate nucleus (LGN) and the primary visual cortex (V1) following presentation of a novel visual stimulus. Here we will selectively manipulate cortical, thalamocortical and corticothalamic neuronal populations in a state specific manner. We will measure both response changes in individual V1 and LGN neurons to the presented stimulus, and behavioral responses to the presented stimulus in the context of a visual discrimination task. We will test whether neurons that are selectively responsive to the visual stimulus play a critical role in guiding network activity patterns during subsequent sleep, acting as an instructive mechanism for circuit plasticity. Finally, we will test whether following visual experience, sleep-dependent communication between V1 and the perirhinal cortex (essential for visual recognition memory) is responsible sleep-dependent discrimination learning.

This proposal is concerned with the design and realization of acoustic metamaterials with nonreciprocal wave propagation protected by the phonon band topology, with special emphasis on the propagation of bulk waves and on the development of classes of control strategies relying on structural mechanisms. The plan towards these goals is articulated along three thrusts: (1) understanding of the fundamental role played by topology on the propagation of waves in spatial-temporally modulated media, which will allow us to mechanically program the band structure of metamaterials to achieve non-reciprocal transport; (2) design of Maxwell-lattice-based metastructures, which will realize oneway transport through mechanically triggered transitions between topological insulator-like and metallike states as well as reconfigurable integrated acoustic circuits; (3) experimental demonstration of the proposed concepts on prototypes at different spatial and complexity scales using the state-of-the-art fabrication techniques and laser-enabled wave reconstruction capabilities of the team.

We propose a program of research that aims to expand the toolset of multidimensional spectroscopies to provide unprecedented sensitivity, spatial resolution and access to dark states to enable in vivo studies of photosynthetic function. Using purple bacteria as a model system this research proposal aims to address the following key open questions: i) What is the physical nature, functional relevance, and true dephasing time of quantum coherence in purple bacteria? ii) How do purple bacteria remodel their energy-landscape to adapt to high and low light conditions? iii) How do purple bacteria adapt their photoprotection mechanisms in aerobic environments? By uncovering photosynthetic design principles in the simpler bacterial systems we aim to pave the way for a better understanding of plant photosystems. Such an understanding is a fundamental pursuit that will enable us to learn from Nature to meet our own energy needs through the development of artificial light-harvesting systems and biofuels.

The basic photosynthetic architecture consists of antenna complexes to harvest solar energy and reaction centers to convert the energy into a stable charge separated state. In oxygenic photosynthesis, the initial charge separation event occurs with near unit quantum efficiency in the photosystem II reaction center (PSII RC). PSII is the only known natural enzyme that uses solar energy to split water, making the elucidation of its design principles critical for our fundamental understanding of photosynthesis and for our ability to mimic PSII’s remarkable properties. The reaction center in purple bacteria (BRC) bears many similarities to the PSII RC but provides a spectroscopically simpler system to study. The charge separation process in the BRC is better understood, making it an appealing model system for developing new experimental and theoretical approaches. This proposal focuses on key deficits in our current understanding of the PSII RC and remaining open questions about the BRC. We propose a synergistic series of experiments on wild-type and mutant RCs and simpler dyad systems aimed at addressing the following questions: 1) What is the electronic structure of the PSII RC and the BRC? 2) What are the charge separation pathways in the PSII RC? 3) Do electronic-vibrational resonances enhance energy transfer and charge separation in the PSII RC and the BRC? The proposed work builds on our previous development of simple and high signal-to-noise approaches to 2D electronic spectroscopy to establish a new multispectral 2D approach that enables a direct view of electronic couplings, energy transfer and charge separation processes over a broad range of frequencies with ultrafast time resolution. By extending 2D spectroscopy into the ultraviolet regime, we will view photosynthetic charge separation from the unique perspective of the protein. By accessing mid-infrared transitions, we will exploit pigment-specific spectroscopic markers to unravel the sequence of charge separation events and gain insight into electronic-vibrational coupling. Combined with the wealth of spectroscopic signatures in the visible-near-infrared regime, Multispectral 2D electronic spectroscopy will provide a rich toolset for addressing the open questions about the PSII RC and BRC. In addition, 2D electronic Stark spectroscopy promises to reveal charge transfer states and their role in charge separation. We will apply our full array of multidimensional tools to wild-type BRCs and PSII RCs to elucidate the role of the different pigments in the electronic structure and charge separation processes. Combined with simulation, these studies will enable us to test and refine electronic structure and charge separation models of the PSII RC, using the BRC as a parallel system in which to test our approach. Multispectral 2D characterization of the coherent dynamics in the BRC and PSII RC mutants, as well as model dyads, will provide insight into the role of electronic-vibrational resonance in enhancing photosynthetic energy transfer and charge separation. These extensive studies of the PSII RC address the fundamental structure-function relationship in this important system to meet the grand challenge of elucidating the design principles used by nature for converting sunlight into chemical energy. The proposed studies will push the development of new methods for simulating multidimensional spectra and refining electronic structure. The newly developed experimental tools will be widely applicable to artificial light-harvesting systems to yield new information about the temporal dynamics and mechanisms of energy transfer and charge separation, giving important experimental feedback for improving their design.

This MURI project aims to greatly expand the new field of active topological mechanical metamaterials (TMMs) by (1) developing 3D printing and self-assembly systems to fabricate TMMs that are addressable at the nanoscale and scalable to the macroscale; (2) expanding fundamental theories of TMMs, especially ones featuring fractional excitations—the new frontier of topological states, by taking advantage of recent advances in knowledge of quantum topological states, the vast majority of which remain uncharted territories for mechanics; (3) using artificial intelligence tools to design and realize continuous media TMMs with no open spaces, which will greatly broaden the structural and functional attributes of TMMs compared to traditional cellular designs; and (4) applying the produced TMMs to realize unidirectional and backscattering-free propagation of waves at previously inaccessible frequency ranges.

The work conducted in the group of co-PI Mao at the University of Michigan will be directed to the theory and simulations of topological mechanics and statistical mechanics of lattice models and stimuli responsive metamaterials. Co-PI Mao, one postdoc, and one graduate student will work together, and in collaborations with other parts of this MURI team, towards the following goals: 1. Theoretical analysis and simulations of nonlinear mechanical response of Maxwell lattices and their topological transitions 2. Theoretical analysis and simulations of statistical mechanics of lattice models at small scales and finite temperature 3. In collaboration with the whole MURI team, optimize designs of stimuli responsive mechanical metamaterials.

How organs control their growth to achieve the correct final size is an enduring mystery of biology. In wild-type Drosophila, for example, left and right-wing areas rarely differ by more than 1%. Here, we aim to decipher the origin of this precision. In particular, we will determine if and how cell competition, cell death, and the hormone Dilp8 cooperate to limit wing size variability. The unexpected discovery of interactions between these systems both constrains their roles in size control and allows sharper experimental probes of these roles. To take advantage of these advances, we will integrate methods from developmental biology with quantitative data analysis and modeling from physics. We will 1) define the time-dependence of normal wing growth and the time windows during which the precited factors act to regulate wing size; 2) quantify spatio-temporal variation of cell density and division and death rates in wildtype and perturbed flies; 3) use mathematical models to translate possible size regulation mechanisms into predictions that can be compared to these measurements and used to inspire new experiments. Our findings will give new insights into organ size control in development.

Epilepsy is one of the world’s most prevalent diseases, yet the rate of uncontrolled seizures has not changed in decades. One of the reasons for this is our limited understanding of seizure mechanisms, and so one of the main goals of epilepsy research is to identify new biomarkers to help us understand the nature of the disease. Recent technological advancements now allow us to monitor brain activity with much higher resolution, which have led to the identification of promising potential biomarkers such as High-Frequency Oscillations (HFOs). Unfortunately, clinicians still have not determined how to utilize this information under clinical conditions. There are three main obstacles to implementing HFOs in practice: 1) they are difficult to find; 2) it is unclear how to ascertain which HFOs are truly related to epilepsy, and 3) it is unclear how to use the HFO data in a prospective fashion to improve clinical care. The purpose of this project is overcome each of these obstacles. In the past funding period, we developed and validated an HFO detection algorithm that overcomes the first obstacle, and allowed us acquire a massive database of HFOs that have opened new avenues of research. In this proposal, we will leverage that algorithm to move HFOs towards clinical translation. In the first Aim, we apply advanced functional connectivity techniques to quantify the network properties of HFOs. Our data, which comprise HFOs from the entire hospitalization and fully curated metadata, are ideal for robust analyses of this new area of HFO research. The second Aim addresses a longstanding, and still unsolved problem in HFO research: how to discern when HFOs are due to epileptic processes versus normal physiology? Our past funding period identified some potential methods to identify pathological HFOs, but also crucial caveats that must be addressed prior to clinical implementation. This Aim will combine multiple classification methods with state-of-the-art machine learning tools to distinguish epileptic from normal HFOs. It will also conduct a large human expert classification of HFOs using clinical EEG software, to start involving epilepsy clinicians in the direct evaluation of HFOs. The third Aim will further develop the translational potential of HFOs, incorporating our unique longitudinal clinical data to characterize the effects of medications, sleep, and other time-varying effects on HFO rates. It will then incorporate these and all prior HFO data into a rigorous latent class model to predict how likely each channel is to be epileptic. These Aims together serve as the framework to establish HFOs as a clinically viable biomarker of seizures, allowing their translation into clinical epilepsy care and leading to future prospective clinical studies using HFOs to guide prospective clinical decisions.

The objective of this project is to elucidate the opportunities presented by topological mechanics for the development of cellular metamaterials exhibiting superior load management capabilities and protection against fracturing. The metamaterials to be investigated are Maxwell lattices, which feature the same number of degrees of freedom and constraints in the bulk and are therefore on the verge of mechanical instability. When these lattices are in their topologically polarized states, they are known to feature topologically protected floppy modes, i.e., states of deformation that do not cost energy, as well as states of self stress, i.e., states of stress that are self-equilibrated without external forces. Both conditions can be established either at the lattice boundaries or along some internal domain walls, or interfaces. When a topological Maxwell lattice featuring domain walls that support states of self stress is loaded and deformed, the stress tends to focus predominantly on these interfaces. This stress focusing can be shown to be preserved even in the presence of cracks in the lattice domain. As a result, the detrimental stress concentration, and subsequently fracturing, that is typically observed at crack tips in classical material systems, can be here avoided or significantly retarded. In essence, the topology endows the lattice with a highly coveted damage-tolerance performance which, in conventional materials, is associated with toughness and typically achieved through material property tuning. The project aims at exposing the potential of topological fracture protection through a holistic investigation that encompasses theoretical, computational and experimental work and takes advantage of the diverse backgrounds and unique testing capabilities of a multidisciplinary team of engineers and physicists. The effort will culminate in the development of a library of lattice architectures featuring fracture protection attributes and validated by experiments based on digital image correlation and acoustic emission.

The interaction of light with matter drives a myriad of fundamental biological processes, with vision and photosynthesis being two prominent examples. Our recent short term collaborative AFOSR grant, of which this is a renewal request, aimed to extract relationships between such processes, via computational and experimental studies. Since light-induced system dynamics takes place in a wide variety of environments (e.g. isomerization in rhodopsin, bacteriorhodopsin, melanopsin, energy transfer in LH1, LH2, FMO, etc.) our focus was on the role of the system-environment interaction in biological function. Theoretical developments during that period, as discussed below, showed a significant parameter sensitivity (PS) of the isomerization quantum yield and of the fluorescence emission to parameter variation in rhodopsin modeling. At the same time, experimental advances now permit rapid and sensitive two-dimensional spectroscopy measurements capable of probing the systemenvironment interaction and PS, prompting the focus of this proposal. Specifically, we plan to computationally and experimentally explore PS and continue system-bath interactions efforts in two light harvesting systems: LH2 and bacteriorhodopsin. Is the PS a common biological characteristic? Is it a manifestation of quantum chaos in Biology? Detailed studies will address the following open questions and issues: 1. What is the origin of parameter sensitivity in rhodopsin? Is it a manifestation of quantum chaos, and/or of Markovian system-environment interactions? 2. Do theoretical models predict parameter sensitivity in isomerization in bacteriorhodopsin and in energy transfer in LH2, and under what conditions? 3. Application of newly developed experimental tools to uncover universal properties of the system-bath interaction in bacteriorhodopsin and LH2 and to observe PS. Initial computational studies will examine the general issues delineated above on the al2 ready well developed rhodopsin model, itself a contribution to our understanding of biological processes. These studies will then be extended to bacteriorhodopsin and LH2. Initial experimental studies will characterize bacteriorhodopsin by coherent and fluorescence-detected two dimensional electronic spectroscopy (F-2DES). These data will be compared with our previous F-2DES studies of LH2 to derive unifying properties of the system-bath interactions in both systems and to explore PS. Leveraging the advances made in implementing F-2DES with digital lock-in detection, efforts to reach the first single molecule F-2DES will be made in LH2.

The objective of the proposed research is to develop and test a new field theoretical framework for the dynamics of soft amorphous solids, which directly connects to the emerging areas of tensor gauge theories and topological mechanics. From collections of grains to aggregates of proteins, colloids or polymers, soft solids have diverse structures and a variety of mechanical features. Examples include glass, cement, compacted sand, and even yogurt or chocolate mousse. Distinct from crystals, soft solids are generically amorphous and often at the margin of mechanical stability, which leads to the adaptability exploited in their applications. Juxtaposed with crystalline elasticity, which emerges from broken translational symmetry, what imparts rigidity to such a wide variety of disordered structures is a puzzle. Elasticity theories are built on principles of momentum (mechanical equilibrium) and energy conservation, from which symmetries, order parameters, geometry and topology of patterns emerge. The absence of energy conservation in marginal soft solids, where dissipative or active processes can be at play, invalidates these theories. In the new framework proposed, conservation principles emerge from just the constraints of mechanical equilibrium. This approach provides a natural way of incorporating the coupling between stress and structural rearrangements inherent in soft solids, which is missing in existing theories, to construct an effective field theory for amorphous materials with string-like stress heterogeneities and localized dynamics.

We propose a program of research that combines extensive expertise in OPV design and characterization with state-of-the-art and emerging multidimensional coherent spectroscopies (MDCS) to understand the energy loss mechanisms that currently limit single junction OPV device efficiencies. Our program has the following primary goals: (i) Gain a fundamental understanding of the mechanisms governing charge and excited state transport and sources of energy loss in NFA-based OPVs (ii) Develop and employ new spectroscopic and visualization techniques that can precisely quantify, on femtosecond - second time scales across the UV and into the infrared, the dynamics of photogenerated charge transfer across heterogeneous interfaces and transport away from their points of origin (iii) Use this understanding to increase the solar-to-electrical power conversion efficiency of NFAbased OPVs to near the thermodynamic limit.

We propose to continue our REU program and invite 7 individuals from around the United States, typically finishing their sophomore or junior year, to participate in a summer research program in Biophysics at the University of Michigan. The site will provide incoming students with a truly unique, interdisciplinary research experience at the intersection of physics, chemistry, mathematics and the life sciences. The Biophysics Program at UM is one of few standalone biophysics programs in the US, created to foster multidisciplinary research and provide interdisciplinary undergraduate and graduate education. It currently has 12 primary and 36 affiliated faculty members, whose labs to which the REU students will have access. Biophysics has a long tradition of interdisciplinary research at the University of Michigan, which positions us ideally to provide this kind of experience to undergraduate students from around the country, in particular from smaller liberal arts colleges and historically minority-serving institutions, who may otherwise have no such access. Since Biophysics is intellectually extremely diverse, our aim is not only to provide research experience in a single subfield of the discipline, but also to provide an overview of the field as a whole. The core component of the program consist of research experience where the students will be assigned to the labs that match their interest and are headed by experienced researchers to participate in innovative scientific exploration. This core will be augmented by weekly research seminars and workshops to expose them to other relevant research topics. We have also designed opportunities for social interactions, which will often be coordinated with other summer undergraduate research programs (Physics and Chemistry REU), to broaden our students’ integration into our scientific and professional communities.

Heme is an essential cofactor for almost every organism in all kingdoms of life. Heme proteins perform a wide range of important biological functions including oxidative metabolism, sensing of diatomic gases, cellular differentiation, gene regulation, protein translation and targeting, and microRNA processing. Heme proteins have also played a unique role in driving our understanding of the structure-function relationship in proteins. Heme proteins remain important model systems to advance our understanding of how nature enables the same cofactor to play vastly different functional roles by careful tuning and coupling of the electronic and vibrational degrees of freedom of the heme and its protein environment. The molecules and mechanisms of heme synthesis, transport, trafficking and signaling remain poorly understood, largely due to the lack of in vivo imaging probes for heme9. This proposal aims to advance our understanding of heme proteins and their diverse biological roles on length scales spanning the molecular to the cellular level. At the molecular level, the proposal aims to uncover design principles used by nature to achieve heme protein functionality, using newly developed multidimensional spectroscopy tools to probe the protein environment and its interactions with the heme cofactor. At the cellular level the proposal aims to exploit the rich multidimensional spectroscopic signatures of heme in its different ligation and redox states as modes of molecular contrast for endogenous multiphoton heme imaging. Specifically the objectives of the proposal are:
Aim
1) Perform the first 2D electronic spectroscopy measurements on heme proteins to uncover functionally-important dynamics for ligand sensing and electron transfer Aim
2) Demonstrate new modes of contrast for in vivo endogenous multidimensional contrast microscopy (MCM) of heme redox and ligand-bound states The two aims of this proposal are highly complementary: the spectroscopic signatures identified in Aim 1) will enable optimization of the contrast to be used for cellular imaging in Aim 2).
The proposed measurements will challenge theoretical and computational approaches to capture the observed quantum and non-equilibrium phenomena. With an understanding of the key design elements of biological systems that exploit quantum effects to optimize their function, it may be possible to mimic such design principles in artificial materials for energy capture, conversion and human use. The proposed research supports technological advances in application areas of interest to the United States Air Force, including bio-molecular and atomic imaging below the diffraction limit, biologically inspired new innovative and novel materials, human performance and enhanced computational development for future Air force needs.