Browsing by Author "Wang, Fan"
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Item Early life height and weight production functions with endogenous energy and protein inputs(Elsevier, 2016) Puentes, Esteban; Wang, Fan; Behrman, Jere R.; Cunha, Flavio; Hoddinott, John; Maluccio, John A.; Adair, Linda S.; Borja, Judith B.; Martorell, Reynaldo; Stein, Aryeh D.We examine effects of protein and energy intakes on height and weight growth for children between 6 and 24 months old in Guatemala and the Philippines. Using instrumental variables to control for endogeneity and estimating multiple specifications, we find that protein intake plays an important and positive role in height and weight growth in the 6ﾖ24 month period. Energy from other macronutrients, however, does not have a robust relation with these two anthropometric measures. Our estimates indicate that in contexts with substantial child undernutrition, increases in protein-rich food intake in the first 24 months can have important growth effects, which previous studies indicate are related significantly to a range of outcomes over the life cycle.Item Modulating Protein Homeostasis to Ameliorate Lysosomal Storage Disorders(2012-09-05) Wang, Fan; Segatori, Laura; Bennett, George N.; Matthews, Kathleen S.; Zygourakis, KyriacosThe goal of this project has been to develop therapeutic strategies for protein misfolding diseases caused by excessive degradation of misfolded proteins and loss of protein function. The focus for this work is lysosomal storage disorders (LSDs), a group of more than 50 known inherited metabolic diseases characterized by deficiency in hydrolytic enzymes and consequent buildup of lysosomal macromolecules. Gaucher’s Disease (GD) is used as a representative of the family of LSDs in this study. GD is caused by mutations in the gene encoding lysosomal glucocerebrosidase (GC) and consequent accumulation of the GC substrate, glucocerebroside. The most prevalent mutations among GD patients are single amino acid substitutions that do not directly impair GC activity, but rather destabilize its native folding. GC normally folds in the ER and trafficks through the secretory pathway to the lysosomes. GC variants containing destabilizing mutations misfold and are retrotranslocated to the cytoplasm for ER-associated degradation (ERAD). However, evidence shows that if misfolding-prone, mutated GC variants are forced to fold into their 3D native structure, they retain catalytic activity. This study describes strategies to remodel the network of cellular pathways that maintain protein homeostasis and to create a folding environment favorable to the folding of unstable, degradation-prone lysosomal enzyme variants. We demonstrated that folding and trafficking of mutated GC variants can be achieved by modulating the protein folding network in fibroblasts derived from patients with GD to i) upregulate the expression of ER luminal chaperones, ii) inhibit the ERAD pathway, and iii) enhance the pool of mutated GC in the ER amenable to folding rescue. We also demonstrated that the same cell engineering strategies that proved successful in rescuing the folding and activity of mutated GC enable rescue of mutated enzyme variants in fibroblasts derived from patients with Tay-Sachs disease, a LSD caused by deficiency of lysosomal hexosaminidase A activity. As a result, the current study provides insights for the development of therapeutic strategies for GD based on the modulation of general cellular pathways that maintain protein homeostasis that could in principle be applied to the treatment of multiple LSDs.Item Reaction Heterogeneities in Lithium Ion Batteries(2021-03-10) Wang, Fan; Tang, MingLithium ion batteries (LIBs) are an indispensable component of personal electronics, electric vehicles, and back-up power source for many critical infrastructures. A series of kinetic processes occur at different length scales within LIBs during their operation. Spatially non-uniform reaction resulting from these processes may lead to inferior performance and even degradation or failure of LIBs. This thesis aims to quantitatively understand the nature of such inhomogeneous phenomena during the operation of LIBs and identify effective ways to prevent their occurrence. At the electrode level, we introduce an analytical model to predict the rate performance of LIBs when reaction non-uniformity results from kinetic limitation in electrolyte transport. The model is built upon the assumption of two prototypical reaction behaviors, uniform vs moving zone reaction, which are idealized based on observations from pseudo two-dimensional (P2D) simulations. Predictions of the analytical model exhibit high accuracy over a wide range of battery design parameters with a computational speed-up of more than 105 times compared to P2D simulations. The model also offers valuable insights on the effects of electrode reaction behavior and cell format (half vs full cells) on the battery cell performance. The analytical model is subsequently applied to optimize battery cell configurations with different objectives, and further extended to consider concentration-dependent electrolyte diffusivity and electrodes with spatially varied properties. Next, we employ a simplified circuit model to elucidate the thermodynamic origin of the reaction heterogeneity within porous electrodes. It is found that the state-of-charge (SOC) dependence of the equilibrium potential of the electrode material strongly influences the degree of reaction non-uniformity across the porous electrode, which can be accurately characterized by a dimensionless parameter deduced from the circuit model. The analysis motivates several potential approaches to mitigating localized reaction in phase-changing electrodes. At the particle level, we employ synchrotron-based transmission X-ray microscopy to study the reaction heterogeneity in LiFePO4 secondary particles. Unlike the core-shell reaction geometry often assumed in literature, we observe ubiquitous stripe-like phase pattern on the secondary particle surface, which is independent of the (dis)charging rate and also persists over a wide range of SOC. The experimentally observations are well captured by phase-field simulations, based on which we suggest that the heterogeneous reaction pathway results from the misfit stress induced by the incompatible volume changes between neighbor primary particles of different crystallographic orientations upon lithium insertion / extraction.Item Remodeling the Proteostasis Network to Rescue Glucocerebrosidase Variants by Inhibiting ER-Associated Degradation and Enhancing ER Folding(Public Library of Science, 2013) Wang, Fan; Segatori, LauraGaucher’s disease (GD) is characterized by loss of lysosomal glucocerebrosidase (GC) activity. Mutations in the gene encoding GC destabilize the protein’s native folding leading to ER-associated degradation (ERAD) of the misfolded enzyme. Enhancing the cellular folding capacity by remodeling the proteostasis network promotes native folding and lysosomal activity of mutated GC variants. However, proteostasis modulators reported so far, including ERAD inhibitors, trigger cellular stress and lead to induction of apoptosis. We show herein that lacidipine, an L-type Ca2+ channel blocker that also inhibits ryanodine receptors on the ER membrane, enhances folding, trafficking and lysosomal activity of the most severely destabilized GC variant achieved via ERAD inhibition in fibroblasts derived from patients with GD. Interestingly, reprogramming the proteostasis network by combining modulation of Ca2+ homeostasis and ERAD inhibition remodels the unfolded protein response and dramatically lowers apoptosis induction typically associated with ERAD inhibition.Item TFEB regulates lysosomal proteostasis(Oxford University Press, 2013) Song, Wensi; Wang, Fan; Savini, Marzia; Ake, Ashley; di Ronza, Alberto; Sardiello, Marco; Segatori, LauraLoss-of-function diseases are often caused by destabilizing mutations that lead to protein misfolding and degradation. Modulating the innate protein homeostasis (proteostasis) capacity may lead to rescue of native folding of the mutated variants, thereby ameliorating the disease phenotype. In lysosomal storage disorders (LSDs), a number of highly prevalent alleles have missense mutations that do not impair the enzyme's catalytic activity but destabilize its native structure, resulting in the degradation of the misfolded protein. Enhancing the cellular folding capacity enables rescuing the native, biologically functional structure of these unstable mutated enzymes. However, proteostasis modulators specific for the lysosomal system are currently unknown. Here, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs. We show that TFEB activation results in enhanced folding, trafficking and lysosomal activity of a severely destabilized glucocerebrosidase (GC) variant associated with the development of Gaucher disease (GD), the most common LSD. TFEB specifically induces the expression of GC and of key genes involved in folding and lysosomal trafficking, thereby enhancing both the pool of mutated enzyme and its processing through the secretory pathway. TFEB activation also rescues the activity of a β-hexosaminidase mutant associated with the development of another LSD, Tay–Sachs disease, thus suggesting general applicability of TFEB-mediated proteostasis modulation to rescue destabilizing mutations in LSDs. In summary, our findings identify TFEB as a specific regulator of lysosomal proteostasis and suggest that TFEB may be used as a therapeutic target to rescue enzyme homeostasis in LSDs.Item Thermodynamic Origin of Reaction Non-Uniformity in Battery Porous Electrodes and Its Mitigation(IOP, 2020) Wang, Fan; Tang, MingThe development of non-uniform reaction current distribution within porous electrodes is a ubiquitous phenomenon during battery charging/discharging and frequently controls the rate performance of battery cells. Reaction inhomogeneity in porous electrodes is usually attributed to the kinetic limitation of mass transport within the electrolyte and/or solid electrode phase. In this work, however, we reveal that it is also strongly influenced by the intrinsic thermodynamic behavior of electrode materials, specifically the dependence of the equilibrium potential on the state of charge: the electrode reaction becomes increasingly non-uniform when the slope of the equilibrium potential curve is reduced. We employ numerical simulations and equivalent circuit model to elucidate such a correlation and show that the degree of reaction inhomogeneity and the resultant discharge capacity can be predicted by a dimensionless reaction uniformity number. For electrode materials that have equilibrium potentials insensitive to the state of charge and exhibit significant reaction non-uniformity, we demonstrate several approaches to spatially homogenizing the reaction current inside porous electrodes, including matching the electronic and ionic resistances, introducing graded electronic conductivity and reducing the surface reaction kinetics.Item Thermodynamic Origin of Reaction Non-Uniformity in Battery Porous Electrodes and Its Mitigation(IOP, 2020) Wang, Fan; Tang, MingThe development of non-uniform reaction current distribution within porous electrodes is a ubiquitous phenomenon during battery charging/discharging and frequently controls the rate performance of battery cells. Reaction inhomogeneity in porous electrodes is usually attributed to the kinetic limitation of mass transport within the electrolyte and/or solid electrode phase. In this work, however, we reveal that it is also strongly influenced by the intrinsic thermodynamic behavior of electrode materials, specifically the dependence of the equilibrium potential on the state of charge: the electrode reaction becomes increasingly non-uniform when the slope of the equilibrium potential curve is reduced. We employ numerical simulations and equivalent circuit model to elucidate such a correlation and show that the degree of reaction inhomogeneity and the resultant discharge capacity can be predicted by a dimensionless reaction uniformity number. For electrode materials that have equilibrium potentials insensitive to the state of charge and exhibit significant reaction non-uniformity, we demonstrate several approaches to spatially homogenizing the reaction current inside porous electrodes, including matching the electronic and ionic resistances, introducing graded electronic conductivity and reducing the surface reaction kinetics.Item Two-dimensional lithium diffusion behavior and probable hybrid phase transformation kinetics in olivine lithium iron phosphate(Springer Nature, 2017) Hong, Liang; Li, Linsen; Chen-Wiegart, Yuchen-Karen; Wang, Jiajun; Xiang, Kai; Gan, Liyang; Li, Wenjie; Meng, Fei; Wang, Fan; Wang, Jun; Chiang, Yet-Ming; Jin, Song; Tang, MingOlivine lithium iron phosphate is a technologically important electrode material for lithium-ion batteries and a model system for studying electrochemically driven phase transformations. Despite extensive studies, many aspects of the phase transformation and lithium transport in this material are still not well understood. Here we combine operando hard X-ray spectroscopic imaging and phase-field modeling to elucidate the delithiation dynamics of single-crystal lithium iron phosphate microrods with long-axis along the [010] direction. Lithium diffusivity is found to be two-dimensional in microsized particles containing ~3% lithium-iron anti-site defects. Our study provides direct evidence for the previously predicted surface reaction-limited phase-boundary migration mechanism and the potential operation of a hybrid mode of phase growth, in which phase-boundary movement is controlled by surface reaction or lithium diffusion in different crystallographic directions. These findings uncover the rich phase-transformation behaviors in lithium iron phosphate and intercalation compounds in general and can help guide the design of better electrodes.