Origin Of Heterogeneity Research Articles

Origin of nanoscale heterogeneity in the surface oxide film protecting stainless steel against corrosion

Stainless steels are widely used as metal components owing to self-protection in aggressive environments, provided by an extremely thin surface oxide film enriched in chromium oxide. Yet, despite decades of research, the mechanisms distributing the chromium enrichment at small length scale are poorly understood, although it may cause loss of stability and local failure of the corrosion resistance. Here, we apply high resolution surface analysis to investigate at small time and length scales the nucleation and growth mechanisms of the surface oxide on a model stainless steel. Starting from an oxide-free surface, we report the direct observation of the oxide nucleation and local oxidation of chromium, which governs the nanoscale heterogeneity of the growing surface oxide by chromium pumping from the atomic terraces to the steps for preferential Cr(III) oxide nucleation and subsequently by segregation from the atomic planes below to grow the Cr(III) layer incompletely saturating the stainless steel surface. This work provides new insight on corrosion chemistry, by evidencing local chemical and structural defects self-generated at the nanoscale by the building process of the protective oxide barrier, and affecting the passive film stability.

Three-state heterogeneity in a model two-dimensional equilibrium liquid

Three structural populations with distinct average mobility are identified within an equilibrium two-dimensional Lennard-Jones fluid simulated via molecular dynamics at a constant temperature and varying density. In particular, quantification of the immediate structural neighborhood of particles by a tessellation allows us to identify three distinct structural states by the shapes of the tessellation cells. Irrespective of dynamic particle exchange among these populations, each population is observed to maintain their own thermodynamic and average dynamic properties across the liquid-solid transition. We expect these findings to be useful in developing a better understanding of the structural origin of dynamical heterogeneity in complex fluids, defined in terms of local mobility fluctuations.

On the Origin of Heterogeneous Diffusion in Glassy Poly(alkyl methacrylates)

ABSTRACTThe diffusion of small molecules through amorphous polymers proceeds by the thermally activated jumps whose rate changes from one region to another due to polymer heterogeneity. Little is known at present about the origin of diffusion heterogeneity. The oxidation of triplet nitrene and quenching of phenanthrene phosphorescence have been used to study the movement of molecular oxygen on a nanometer length scale in glassy poly(ethyl methacrylate) and poly(n‐butyl methacrylate) far below the glass transition temperature. It has been found that, as temperature increases, the jump rates in all regions increase by the same factor. This finding points to the equality of the activation energies of oxygen jumps in different regions of the polymers. We conclude that the correlated elastic displacements of polymer chains inside regions about several nanometers in size provide molecules jumps. Due to the large size of these regions, the activation energy of jump does not depend on local polymer structure. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2019, 57, 1097–1104

2019 Leonard Medal to Hisayoshi Yurimoto

2019 Leonard Medal to Hisayoshi Yurimoto

Abstract 2900: Dissection of clonal heterogeneity unmasks pre-existing chemoresistance and new metabolic vulnerabilities in pancreatic cancer

Abstract Adaptive drug-resistance mechanisms allow human tumors to evade treatment through selection and expansion of treatment-resistant clones. Modeling the functional heterogeneity of tumors can unmask critical contributions of distinct tumor cell sub-populations toward identifying rational drug combinations. Here, studying clonal evolution of tumor cells derived from human pancreatic tumors, we demonstrate that in vitro adherent cultures and in vivo tumors are maintained by a common set of long term self-renewing tumorigenic cells that can be used to establish clonal replica tumors (CRTs), large cohorts of animals bearing human tumors with identical clonal composition. Using CRTs to conduct quantitative assessments of clonal dynamics and adaptive responses to therapeutic challenge over time, we uncovered that the tumorigenic compartment of pancreatic tumors maintains a multitude of functionally heterogeneous subpopulations of cells with differential degrees of sensitivity to therapeutics. High-throughput isolation and deep characterization of unique clonal lineages showed genetic and transcriptomic diversity underlying the functionally diverse subpopulations, positioning the origins of tumor heterogeneity within the long-term self-renewing compartment. Molecular annotation of gemcitabine-naïve clonal lineages with distinct responses to treatment in the context of CRTs generated signatures that can predict the response to chemotherapy and exposed pre-existing functional mechanisms of clonal resistance, primarily associated to DNA damage tolerance and mitochondrial respiration (OXPHOS). Further transcriptomic and metabolic characterization of residual tumor cells in patient derived xenograft models as well as in patients after chemoradiation showed that resistant cells that contribute to tumor relapse are metabolically rewired to upregulate OXPHOS. Combining a novel inhibitor of oxidative phosphorylation (IACS-10759) developed at the MD Anderson Institute for Applied Cancer Science, and currently in phase I clinical trial in acute myeloid leukemia and solid tumors, with standard of care drugs drastically reduces tumor clonal complexity, underscoring the promise of inhibiting mitochondrial respiration as a new therapeutic strategy to prolong patient survival by eradicating resistant clones that survive chemoradiation. Our study, correlating genomic and transcriptomic traits with specific functional phenotypes, uncovered new mechanisms that underlie intra-tumor sub-clonal heterogeneity, influence treatment response to drugs and sustain tumor relapse. Citation Format: Sahil Seth, Chieh-Yuan Li, Sara Loponte, I-Lin Ho, Denise Corti, Luigi Sapio, Edoardo Del Poggetto, Michael Peoples, Tatiana Karpinets, Frederick S. Robinson, Shan Jiang, Prasanta Dutta, Joseph Marszalek, Maria E. Di Francesco, Timothy P. Heffernan, Virginia Giuliani, Pratip K. Bhattacharya, Giannicola Genovese, Andrew Futreal, Giulio Draetta, Andrea Viale, Alessandro Carugo. Dissection of clonal heterogeneity unmasks pre-existing chemoresistance and new metabolic vulnerabilities in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2900.

Non-Gaussian diffusion of mixed origins

The properties of diffusion processes are drastically affected by heterogeneities of the medium that can induce non-Gaussian behavior of the propagator in contrast with the idealized realm of Brownian motion. In this paper we analyze the diffusion propagator when distinct origins of heterogeneity (e.g. time-fractional diffusion, diffusing diffusivity, distributed diffusivity across a population) are combined. These combinations allow one to describe new classes of strongly heterogeneous processes relevant to biology. Based on a combined subordination technique, we obtain the exact propagator for different instructive examples. This approach is then used to calculate analytically the first-passage time statistics (on half-real line and in any bounded domain) for a particle undergoing non-Gaussian diffusion of mixed origins.

Microstructure of nonideal methanol binary liquid mixtures.

The nonideality of binary mixtures is often related to the nature of the interactions between both liquids and of the heterogeneity at the nanoscale-named microstructure. When one of the liquids is a hydrogen bonds former and the second is aprotic, the progressive diluting of the hydrogen-bonding network leads to a clustering and nanophases. By considering two mixtures, toluene-methanol and cyclohexane-methanol, the nonideality and its connection with the structure at the nanoscale and the intermolecular interactions are numerically investigated. Contrary to the toluene that is fully miscible in methanol, cyclohexane presents a high range of immiscibility which makes it a relevant system to study the nucleation (local segregation) and its propagation. In both mixtures, the deviation from the ideal behavior is observed. In the case of the toluene-methanol mixture, the initial hydrogen-bonding network corresponding to a homogenous structure is locally broken due to the favorable toluene-methanol interactions leading to the spatial heterogeneity at the origin of the nonideality. In the range of miscibility of the cyclohexane-methanol mixtures, the formation of hydrophobic nanophases of larger size is observed due to the unfavorable interactions between both components leading to a self-organizing of cyclohexane molecules. The immiscibility of cyclohexane and methanol are then correlated to the formation of nanophases and their propagation, which are also at the origin of the spatial heterogeneity. In the pure methanol, we highlight the disconnection between the clustering and the heterogeneity. We shed light on the fact that the prepeak observed in the structure factor is independent of the degree of heterogeneity, but is connected to the presence of cyclic clusters.

The Prevalence of Posttraumatic Stress Disorder Among Survivors After a Typhoon or Hurricane: A Systematic Review and Meta-Analysis.

Posttraumatic stress disorder (PTSD) is a psychological disorder, which could be caused by traumatic events. The prevalence of PTSD among survivors after a typhoon or hurricane varied widely. Therefore, this study aimed to determine a combined prevalence of PTSD among survivors after a typhoon or hurricane. A systematic search of literature was performed in the 3 English databases: PubMed (National Library of Medicine, Bethesda, MD), ISI Web of Science (Thomson Reuters, New York, NY), and Embase (Elsevier, Amsterdam, Netherlands). Also, a similar search was performed in the 2 Chinese databases such as Chinese National Knowledge Infrastructure and WanFang. Loney et al.'s criteria were used to evaluate the quality of the selected articles for this study. The combined prevalence of PTSD among the study population was estimated using the Freeman-Tukey double arcsine transformation method. Subgroup analyses and a meta-regression analysis were carried out to explore the origin of heterogeneity. Thirty-nine eligible articles were included in this study. They comprised 43 123 typhoon and hurricane survivors of which 9373 were diagnosed with PTSD. The combined prevalence of PTSD among this population was 17.81%. Subgroup analyses revealed that the combined prevalence of PTSD related to typhoon and hurricane Categories 5, 4, and 2 showing a corresponding decreasing tendency. About 18% of people who experienced a severe typhoon or hurricane develop PTSD with the prevalence decreasing with reduced severity of the typhoon or hurricane.

The Origin of Metal Loading Heterogeneities in Pt/Zeolite Y Bifunctional Catalysts.

Preparing catalysts with highly dispersed metal nanoparticles and narrow particle size distribution has been in the focus of numerous studies. Besides size and size distribution, the location of metal nanoparticles within and local metal loading of the support can have significant impact on catalytic performance. This study revealed that great variations in Pt loading between individual Pt/zeolite Y crystals occurred irrespective of the metal deposition method, namely ion‐exchange (IE) or incipient wetness impregnation (IWI). The variation in Pt loading was found to be directly related to different Si/Al ratios of individual zeolite crystals. Results indicate that this Si/Al variation was likely induced by post‐synthesis treatments, commonly performed to introduce mesoporosity. In view of the great importance of zeolite‐based catalysts for oil refining, understanding the origin of such metal loading heterogeneities may lead to further improvement of zeolite‐based catalytic performance.

Biological composition and microbial dynamics of sinking particulate organic matter at abyssal depths in the oligotrophic open ocean

Sinking particles are a critical conduit for the export of organic material from surface waters to the deep ocean. Despite their importance in oceanic carbon cycling and export, little is known about the biotic composition, origins, and variability of sinking particles reaching abyssal depths. Here, we analyzed particle-associated nucleic acids captured and preserved in sediment traps at 4,000-m depth in the North Pacific Subtropical Gyre. Over the 9-month time-series, Bacteria dominated both the rRNA-gene and rRNA pools, followed by eukaryotes (protists and animals) and trace amounts of Archaea. Deep-sea piezophile-like Gammaproteobacteria, along with Epsilonproteobacteria, comprised >80% of the bacterial inventory. Protists (mostly Rhizaria, Syndinales, and ciliates) and metazoa (predominantly pelagic mollusks and cnidarians) were the most common sinking particle-associated eukaryotes. Some near-surface water-derived eukaryotes, especially Foraminifera, Radiolaria, and pteropods, varied greatly in their abundance patterns, presumably due to sporadic export events. The dominance of piezophile-like Gammaproteobacteria and Epsilonproteobacteria, along with the prevalence of their nitrogen cycling-associated gene transcripts, suggested a central role for these bacteria in the mineralization and biogeochemical transformation of sinking particulate organic matter in the deep ocean. Our data also reflected several different modes of particle export dynamics, including summer export, more stochastic inputs from the upper water column by protists and pteropods, and contributions from sinking mid- and deep-water organisms. In total, our observations revealed the variable and heterogeneous biological origins and microbial activities of sinking particles that connect their downward transport, transformation, and degradation to deep-sea biogeochemical processes.

Macrophages in bacterial lung diseases: phenotype and functions (review)

This literature review is devoted to the analysis of the role of macrophages in the immunopathogenesis of infectious lung diseases of bacterial etiology. The article summarizes information about the origin of macrophages, their phenotypic and functional heterogeneity. The mechanisms of impaired protective function of innate immunity are associated with the polarization of the program of maturation and activation of macrophages in the direction to tolerogenic or immunoregulatory cells with phenotype of M2. Alveolar macrophages perform a variety of functions (from pro-inflammatory to regenerative) in the development of inflammation in the respiratory organs. Their inherent plasticity suggests that the same macrophages can change their phenotype and function depending on the microenvironment in the inflammatory focus at different stages of the disease. Understanding the mechanisms that regulate macrophage plasticity will be an important step towards realizing the potential of personalized immunomodulatory therapy.

Understand and Mitigate Reaction Non-Uniformity in Battery Electrodes

Reaction non-uniformity develops in battery electrodes across a wide range of length scales from the electrode to agglomerate and primary particle level. The resultant non-uniform state of charge distribution increases polarization and reduces energy utilization and rate performance. It generates incompatible volume changes, which triggers microcracks and dislocations. Inhomogeneous intercalation could cause overheating at local spots of high current density and also over-charge/discharge, which leads to irreversible structure decomposition and capacity fading. Understanding the origins of reaction heterogeneity and identifying its mitigation strategy is critical for developing better and safer batteries. In this work, we use mesoscale theory and simulation to elucidate a few important factors in the development of non-uniform reaction distribution at different length scales. At the single particle level, we show that misfit stress generated by lattice mismatch between the lithiated and delithiated phases plays an important role in inducing non-uniform (de)intercalation front through two general mechanisms. The first mechanism, referred to as “surface-mode coherent spinodal decomposition”, occurs in systems that undergo spontaneous phase separation such as olivine LiFePO4. We use phase-field simulation to reveal the morphological evolution of intercalation front in LiFePO4 under stress influence, which satisfactorily explains recent in-situ experimental observations. The second mechanism, which we refer to as “inverted Grinfeld instability”, is analogous to the well-known Asaro-Tiller-Grinfeld instability in epitaxial thin film growth and applies to electrode materials such as Li(Ni0.5Mn1.5)O4 with first-order phase transformations upon cycling. We employ linear stability analysis to establish the criteria of interface instability and construct interface stability diagrams in the space of particle size, applied overpotential / flux and interface location, from which the conditions for achieving uniform intercalation can be identified. At the electrode level, we identify electrolyte depletion as a major factor contributing to reaction inhomogeneity especially at large electrode thickness. By analyzing battery (dis)charge kinetics in the framework of porous electrode theory, two types of non-uniform reaction behavior are discovered for electrode systems that exhibit solid-solution-like (e.g. NMC) or phase-changing (e.g. LiFePO4, Li4Ti5O12) intercalation behavior, respectively. A simplified analytical model was developed to quantitatively describe such behaviors, which shows very good agreement with numerical simulations and provides an efficient tool for predicting reaction distribution within composite electrodes. We further elucidate the coupled effects of ionic and electronic conductivities and surface reaction kinetics on reaction uniformity through a simplified circuit model. Based on the theoretical understanding, we suggest that balancing the kinetic competition between electrolyte transport, electronic conduction and surface reactions represents an effective strategy to promote homogeneous reaction in thick battery electrodes.

Velocity and density characteristics of subducted oceanic crust and the origin of seismic heterogeneity in the lower mantle

Velocity and density characteristics of subducted oceanic crust and the origin of seismic heterogeneity in the lower mantle

Single Nanoparticle Electrochemistry.

Experimental techniques to monitor and visualize the behaviors of single nanoparticles have not only revealed the significant spatial and temporal heterogeneity of those individuals, which are hidden in ensemble methods, but more importantly, they have also enabled researchers to elucidate the origin of such heterogeneity. In pursuing the intrinsic structure-function relations of single nanoparticles, the recently developed stochastic collision approach demonstrated some early promise. However, it was later realized that the appropriate sizing of a single nanoparticle by an electrochemical method could be far more challenging than initially expected owing to the dynamic motion of nanoparticles in electrolytes and complex charge-transfer characteristics at electrode surfaces. This clearly indicates a strong necessity to integrate single nanoparticle electrochemistry with high-resolution optical microscopy. Hence, this review aims to give a timely update of the latest progress for both electrochemically sensing and seeing single nanoparticles. A major focus is on collision-based measurements, where nanoparticles or single entities in solution impact on a collector electrode and the electrochemical response is recorded. These measurements are further enhanced with optical measurements in parallel. For completeness, advances in other related methods for single nanoparticle electrochemistry are also included.

Prognostic impact of galectin-3 in chronic kidney disease patients: a systematic review and meta-analysis.

Galectin-3 as a β-galactoside-binding lectin, which has served important functions in numerous biological activities including cell growth, apoptosis, pre-mRNA splicing, differentiation, transformation, angiogenesis, inflammation, fibrosis, and host defense, may be used in prediction of clinical outcomes in CKD patients. However, the given results remain debatable and inconclusive. Hence, we performed a comprehensive meta-analysis to clarify the predictive value of galectin-3 in patients with CKD, especially ESRD patients going on dialysis. PubMed and Embase electronic databases were searched to identify eligible studies reporting the association between galectin-3 and adverse outcomes in CKD patients. We searched the literatures published October 2018 or earlier. We used both fix-effects and random-effects models to calculate the overall effect estimate. An I2 > 50% indicates at least moderate statistical heterogeneity. A sensitivity analysis and subgroup analysis were performed to find the origin of heterogeneity. We ultimately enrolled five studies with a total of 5226 patients in this meta-analysis. The result showed that high galectin-3 levels were associated with increased risk of all-cause mortality and cardiovascular (CV) events in CKD patients. For every 1% increased in galectin-3, the risk of all-cause mortality increased by 37.9% (HR 1.379, 95% CI 1.090-1.744). Much more, the risk of CV events in CKD patients was also significantly increased (HR 1.054, 95% CI 1.007-1.102) with no statistical heterogeneity among the studies (I2 = 0.0%, p = 0.623). However, there was no statistical difference between the risk of all-cause mortality and galectin-3 in HD patients (HR 1.171, 95% CI 0.963-1.425). Our meta-analysis suggests that high levels of galectin-3 may increase the risk of all-cause mortality and CV events in CKD patients, however, probably not a sensitive biomarker for outcomes in HD patients. Further studies were warranted to validate our findings.

Flap valve of the heart foramen ovale revisited: macroscopic and histologic observations of human near-term fetuses

We assessed the flap valve of the foramen ovale (FO valve) by examining 30 hearts from human fetuses of gestational age 30–40 weeks. We dissected the hearts, examined their macroscopic morphology, and then prepared semiserial sagittal sections across the valve. Although the primary septum is expected to extend along the left atrial face, eight hearts had a superior rim of the fossa ovalis on the left atrial face that was too thick and high, so there was no smooth continuation with the valve. Moreover, three of these eight hearts each had a flap valve that was fused with a long and narrow plate arising from the caval orifice. Histological analysis indicated that 21 specimens each had a candidate primary septum that contained myocardium, although the left sinuatrial valve (LSAV) contained fibrous tissue, but little or no myocardium. In each of 17 hearts, a candidate primary septum was attached to the left atrial face of the fossa, and parts of the LSAV extended to and approached the right atrial face. However, seven of these 17 hearts each had a folded small primary septum. Another four of these 17 hearts each had an LSAV that extended widely to the fossa, and a candidate primary septum (which might be a remnant) attached to the left atrial side of the LSAV. These variations suggest that the LSAV makes a major contribution to the FO valve in some fetal hearts. Consequently, the fetal FO valve appears to have heterogeneous morphology and origin.

Independent Microevolution Mediated by Mobile Genetic Elements of Individual Clostridium difficile Isolates from Clade 4 Revealed by Whole-Genome Sequencing.

Horizontal gene transfer of mobile genetic elements (MGEs) accounts for the mosaic genome of Clostridium difficile, leading to acquisition of new phenotypes, including drug resistance and reconstruction of the genomes. MGEs were analyzed according to the whole-genome sequences of 37 C. difficile isolates with a variety of sequence types (STs) within clade 4 from China. Great diversity was found in each transposon even within isolates with the same ST. Two novel transposons were identified in isolates ZR9 and ZR18, of which approximately one third to half of the genes showed heterogenous origins compared with the usual intestinal bacterial genes. Most importantly, catD, known to be harbored by Tn4453a/b, was replaced by aac(6') aph(2'') in isolates 2, 7, and 28. This phenomenon illustrated the frequent occurrence of gene exchanges between C. difficile and other enterobacteria with individual heterogeneity. Numerous prophages and CRISPR arrays were identified in C. difficile isolates of clade 4. Approximately 20% of spacers were located in prophage-carried CRISPR arrays, providing a new method for typing and tracing the origins of closely related isolates, as well as in-depth studies of the mechanism underlying genome remodeling. The rates of drug resistance were obviously higher than those reported previously around the world, although all isolates retained high sensitivity to vancomycin and metronidazole. The increasing number of C. difficile isolates resistant to all antibiotics tested here suggests the ease with which resistance is acquired in vivo. This study gives insights into the genetic mechanism of microevolution within clade 4. IMPORTANCE Mobile genetic elements play a key role in the continuing evolution of Clostridium difficile, resulting in the emergence of new phenotypes for individual isolates. On the basis of whole-genome sequencing analysis, we comprehensively explored transposons, CRISPR, prophage, and genetic sites for drug resistance within clade 4 C. difficile isolates with different sequence types. Great diversity in MGEs and a high rate of multidrug resistance were found within this clade, including new transposons, Tn4453a/b with aac(6') aph(2'') instead of catD, and a relatively high rate of prophage-carried CRISPR arrays. These findings provide important new insights into the mechanism of genome remodeling within clade 4 and offer a new method for typing and tracing the origins of closely related isolates.

Microscopic insights into dynamical heterogeneity in a lane forming colloid

Microscopic origin of dynamical heterogeneity (DH) in non-equilibrium systems has been a topic of profound interest over the last decades. However, the theoretical description of DH has been debated for it lacks a structural description. Using Brownian Dynamics simulations, in a model lane forming system of constantly driven charged binary colloidal suspension, we explore DH in terms of multiple relaxing partial structures between particles of different mobilities that relax at different rates and have distinct lifetimes of structural relaxation. Further, we show that the heterogeneity in structural relaxation maximizes when effective poly-dispersity has a maximum.

Single cell RNA-seq identifies the origins of heterogeneity in efficient cell transdifferentiation and reprogramming.

Forced transcription factor expression can transdifferentiate somatic cells into other specialised cell types or reprogram them into induced pluripotent stem cells (iPSCs) with variable efficiency. To better understand the heterogeneity of these processes, we used single-cell RNA sequencing to follow the transdifferentation of murine pre-B cells into macrophages as well as their reprogramming into iPSCs. Even in these highly efficient systems, there was substantial variation in the speed and path of fate conversion. We predicted and validated that these differences are inversely coupled and arise in the starting cell population, with Mychigh large pre-BII cells transdifferentiating slowly but reprogramming efficiently and Myclow small pre-BII cells transdifferentiating rapidly but failing to reprogram. Strikingly, differences in Myc activity predict the efficiency of reprogramming across a wide range of somatic cell types. These results illustrate how single cell expression and computational analyses can identify the origins of heterogeneity in cell fate conversion processes.

Spatiotemporal regulation of clonogenicity in colorectal cancer xenografts

Cancer evolution is predominantly studied by focusing on differences in the genetic characteristics of malignant cells within tumors. However, the spatiotemporal dynamics of clonal outgrowth that underlie evolutionary trajectories remain largely unresolved. Here, we sought to unravel the clonal dynamics of colorectal cancer (CRC) expansion in space and time by using a color-based clonal tracing method. This method involves lentiviral red-green-blue (RGB) marking of cell populations, which enabled us to track individual cells and their clonal outgrowth during tumor initiation and growth in a xenograft model. We found that clonal expansion largely depends on the location of a clone, as small clones reside in the center and large clones mostly drive tumor growth at the border. These dynamics are recapitulated in a computational model, which confirms that the clone position within a tumor rather than cell-intrinsic features, is crucial for clonal outgrowth. We also found that no significant clonal loss occurs during tumor growth and clonal dispersal is limited in most models. Our results imply that, in addition to molecular features of clones such as (epi-)genetic differences between cells, clone location and the geometry of tumor growth are crucial for clonal expansion. Our findings suggest that either microenvironmental signals on the tumor border or differences in physical properties within the tumor, are major contributors to explain heterogeneous clonal expansion. Thus, this study provides further insights into the dynamics of solid tumor growth and progression, as well as the origins of tumor cell heterogeneity in a relevant model system.