Origin Of Heterogeneity Research Articles

Signaling Heterogeneity is Defined by Pathway Architecture and Intercellular Variability in Protein Expression

SummaryInsulin's activation of PI3K/Akt signaling, stimulates glucose uptake by enhancing delivery of GLUT4 to the cell surface. Here we examined the origins of intercellular heterogeneity in insulin signaling. Akt activation alone accounted for ~25% of the variance in GLUT4, indicating that additional sources of variance exist. The Akt and GLUT4 responses were highly reproducible within the same cell, suggesting the variance is between cells (extrinsic) and not within cells (intrinsic). Generalized mechanistic models (supported by experimental observations) demonstrated that the correlation between the steady-state levels of two measured signaling processes decreases with increasing distance from each other and that intercellular variation in protein expression (as an example of extrinsic variance) is sufficient to account for the variance in and between Akt and GLUT4. Thus, the response of a population to insulin signaling is underpinned by considerable single-cell heterogeneity that is largely driven by variance in gene/protein expression between cells.

Insights on the Control of Yeast Single-Cell Growth Variability by Members of the Trehalose Phosphate Synthase (TPS) Complex.

Single-cell variability of growth is a biological phenomenon that has attracted growing interest in recent years. Important progress has been made in the knowledge of the origin of cell-to-cell heterogeneity of growth, especially in microbial cells. To better understand the origins of such heterogeneity at the single-cell level, we developed a new methodological pipeline that coupled cytometry-based cell sorting with automatized microscopy and image analysis to score the growth rate of thousands of single cells. This allowed investigating the influence of the initial amount of proteins of interest on the subsequent growth of the microcolony. As a preliminary step to validate this experimental setup, we referred to previous findings in yeast where the expression level of Tsl1, a member of the Trehalose Phosphate Synthase (TPS) complex, negatively correlated with cell division rate. We unfortunately could not find any influence of the initial TSL1 expression level on the growth rate of the microcolonies. We also analyzed the effect of the natural variations of trehalose-6-phosphate synthase (TPS1) expression on cell-to-cell growth heterogeneity, but we did not find any correlation. However, due to the already known altered growth of the tps1Δ mutants, we tested this strain at the single-cell level on a permissive carbon source. This mutant showed an outstanding lack of reproducibility of growth rate distributions as compared to the wild-type strain, with variable proportions of non-growing cells between cultivations and more heterogeneous microcolonies in terms of individual growth rates. Interestingly, this variable behavior at the single-cell level was reminiscent to the high variability that is also stochastically suffered at the population level when cultivating this tps1Δ strain, even when using controlled bioreactors.

Leukocyte Trafficking and Hemostasis in the Mouse Fetus in vivo: A Practical Guide.

In vivo observations of blood cells and organ compartments within the fetal mammalian organism are difficult to obtain. This practical guide describes a mouse model for in vivo observation of the fetal yolk-sac and corporal microvasculature throughout murine gestation, including imaging of various organ compartments, microvascular injection procedures, different methods for staining of blood plasma, vessel wall and circulating cell subsets. Following anesthesia of pregnant mice, the maternal abdominal cavity is opened, the uterus horn exteriorized, and the fetus prepared for imaging while still connected to the placenta. Microinjection methods allow delivery of substances directly into the fetal circulation, while substances crossing the placenta can be easily administered via the maternal circulation. Small volume blood sample collection allows for further in vitro workup of obtained results. The model permits observation of leukocyte-endothelial interactions, hematopoietic niche localization, platelet function, endothelial permeability studies, and hemodynamic changes in the mouse fetus, using appropriate strains of fluorescent protein expressing reporter mice and various sophisticated intravital microscopy techniques. Our practical guide is of interest to basic physiologists, developmental biologists, cardiologists, and translational neonatologists and reaches out to scientists focusing on the origin and regulation of hematopoietic niches, thrombopoiesis and macrophage heterogeneity.

Petrology, geochemistry, Ar[sbnd]Ar isotopes of an arc related calk-alkaline pluton from Mamb (Pan-African Yaounde group, Cameroon): A testimony to the subduction of a hot oceanic crust

In Central Africa, the Pan-African Yaoundé group is made up of migmatites and gneisses exhumed and thrusted on micaschists. In a window in the micaschists, the Mamb metagabbro massif occurs as km-size and ca 20 m-high hill crosscut by a 15 m-thick dyke of meta-hornblendite. Minor facies are biotitites, garnetites, and granitic veins. Metagabbro comprises pargasite, biotite, labrador-andesine, pyrope- andradite- grossular-rich almandine, epidote, FeTi oxide, quartz, scapolite, rutile, zircon, and late metamorphic muscovite, whereas meta-hornblendite is made up of abundant edenite-pargasite, and minor amounts of plagioclase, biotite and epidote. Textural features such as epidote needles in plagioclase and rutile exsolutions in amphibole suggests that metamorphism (P-T conditions: 610 °C and 9.1 Kb) post-dated magma emplacement and crystallisation. Based on 40Ar/39Ar thermochronology of amphibole and micas, the proceedings of metamorphic processes extended from 601 to 586 Ma. Chemically, metagabbros and meta-hornblendites display hybrid adakitic and calk-alkaline characteristics. Mantle-normalised element patterns of metagabbros are marked by negative Nb, Ta, Zr, Hf, Ti, Y and positive Sr and Pb anomalies parallel to metadiorites of Yaoundé. Meta-hornblendite patterns show depletion in Th, K, and Pb similarly to alkaline rocks but high values of Y/Nb (> 3) and Zr/Nb (11–52) ratios point to a subalkalic affinity. Characteristics of these metagabbros and meta-hornblendites point to heterogeneous origins by partial melting of a dehydrated subducted hot oceanic crust and the fusion of a metasomatised mantle wedge. Metadiorites from Yaoundé are arc related rocks. Thus it appears that the island arc setting described at Boumnyebel extends eastwards up to Yaoundé, and probably up to Lomié in the south-eastern Cameroon. The northwards extension of this setting is yet to be established taking into account the presence of Archaean-Paleoproterozoic formations north of the continental scale Sanaga shear zone. At the regional scale, the best model to explain the presence of adakites and classic arc magmas at Mamb, Bape, Bangangté and Fomopea is a south-north subduction of the Pan-African Yaoundé hot oceanic crust under the Archaean Adamawa-Yade block.

Integrated decoding hematopoiesis and leukemogenesis using single-cell sequencing and its medical implication

Single-cell RNA sequencing provides exciting opportunities to unbiasedly study hematopoiesis. However, our understanding of leukemogenesis was limited due to the high individual differences. Integrated analyses of hematopoiesis and leukemogenesis potentially provides new insights. Here we analyzed ~200,000 single-cell transcriptomes of bone marrow mononuclear cells (BMMCs) and its subsets from 23 clinical samples. We constructed a comprehensive cell atlas as hematopoietic reference. We developed counterpart composite index (CCI; available at GitHub: https://github.com/pengfeeei/cci) to search for the healthy counterpart of each leukemia cell subpopulation, by integrating multiple statistics to map leukemia cells onto reference hematopoietic cells. Interestingly, we found leukemia cell subpopulations from each patient had different healthy counterparts. Analysis showed the trajectories of leukemia cell subpopulations were similar to that of their healthy counterparts, indicating that developmental termination of leukemia initiating cells at different phases leads to different leukemia cell subpopulations thus explained the origin of leukemia heterogeneity. CCI further predicts leukemia subtypes, cellular heterogeneity, and cellular stemness of each leukemia patient. Analyses of leukemia patient at diagnosis, refractory, remission and relapse vividly presented dynamics of cell population during leukemia treatment. CCI analyses showed the healthy counterparts of relapsed leukemia cells were closer to the root of hematopoietic tree than that of other leukemia cells, although single-cell transcriptomic genetic variants and haplotype tracing analyses showed the relapsed leukemia cell were derived from an early minor leukemia cell population. In summary, this study developed a unified framework for understanding leukemogenesis with hematopoiesis reference, which provided novel biological and medical implication.

Antiosteoporosis Effect and Possible Mechanisms of the Ingredients of Fructus Psoraleae in Animal Models of Osteoporosis: A Preclinical Systematic Review and Meta-Analysis.

Objective Fructus Psoraleae (FP) and its ingredients (IFP) have a variety of biological activities and are widely used to treat osteoporosis (OP). Herein, we conducted a systematic review to evaluate the efficacy of IFP for an animal model of OP from the current literatures. Potential mechanisms of IFP in the treatment of OP were also summarized. Materials and Methods We carried out a search for electronic literature in the PubMed, Chinese National Knowledge Infrastructure, EMBASE, Wanfang, Web of Science, Chinese Biomedical Literature Database, and Cochrane Library, as well as Chinese VIP databases targeting articles published from inception to June 2021. The inclusion criteria were animal studies that assessed the efficacy and safety of IFP for OP, regardless of publication status or language. The exclusion criteria included (1) other types of studies (in vitro studies, case reports, clinical trials, reviews, abstracts, comments, and editorials), (2) combination with other compounds, (3) compared with other traditional Chinese medicine, (4) not osteoporosis or bone loss model, (5) studies with insufficient data, (6) lack of a control group, and (7) duplicate publications. The modified Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Stroke (CAMARADES) 10-item quality checklist was used to evaluate the risk of bias of included studies. We computed the relative risk (RR) and the standard mean difference (SMD) for dichotomous outcomes and continuous outcomes, respectively. When heterogeneity was detected or there was significant statistical heterogeneity (P < 0.05 or I2 > 50%), a random-effects model was employed, followed by further subgroup analysis and metaregression estimations to ascertain the origins of heterogeneity. Otherwise, we used a fixed-effects model (P ≥ 0.05 or I2 ≤ 50%). The primary outcome measures were bone mineral density (BMD), serum osteocalcin(S-OCN), bone volume over total volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), bone maximum load, and elasticity modulus. The secondary outcome measure was the antiosteoporosis mechanisms of IFP. The STATA 12.0 software was used to analyze the data. Results Overall, 16 studies focusing on 379 animals were enrolled into the study. The risk of bias score of included studies ranged from 4 to 7 with an average score of 5.25. The present study provided the preliminary preclinical evidence that administration of IFP could significantly increase the S-OCN, BMD, BV/TV, and Tb.N while Tb.Th and Tb.Sp were remarkably decreased by IFP in OP model animals (P < 0.05). Moreover, IFP could significantly improve the bone biomechanical indicator bone maximum load and elasticity modulus (P < 0.05). In terms of the possible mechanisms of treatment of OP, IFP exerts anti-OP effects in animal models probably through osteoprotegerin/receptor activator of the nuclear factor-κB ligand/receptor activator of nuclear factor-κB (OPG/RANKL/RANK), peroxisome proliferator activated receptor γ (PPAR-γ)/Axin2/Wnt, antioxidative stress via forkhead box O3a (FoxO3a)/Axin2/Wnt, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), estrogen-like effect, and gamma-aminobutyric acid/gamma-aminobutyric acid receptor (GABA/GABABRI) signaling pathway. Conclusion Taken together, the findings suggest the possibility of developing IFP as a drug or an ingredient in diet for the clinical treatment of OP. We recommend that rigorous, as well as high-quality, trials involving large sample sizes should be conducted to confirm our findings.

Self-Adaptative Troubleshooting for to Guide Resolution of Malfunctions in Aircraft Manufacturing

The increasing complexity of systems and the heterogeneous origin of the possible malfunctions bring about the necessity of redefining the troubleshooting processes. Troubleshooting comprises the set of steps for the systematic analysis of the symptoms after the detection of a malfunction. The complexity of certain systems, such as aircraft, means the origin of that malfunction can be any of several reasons, where diagnosis techniques support engineers in determining the reason for the unexpected behaviour. However, derived from the high number of components involved in an aircraft, the list of possible fault origins can be extremely long, and the analysis of every element on the list, until the element responsible is found, can be very time-consuming and error-prone. As an alternative, certain input/output signals can be read to prevent the substitution of a correctly functioning component, by validating its behaviour in an indirect way. In order to optimise the actions to perform, we have identified the relevant parts of the model to propose a troubleshooting process to ascertain the signals to read and the components to substitute, while striving to minimise the action cost in accordance with a combination of structural analysis, the probability of malfunction associated to the components, and the cost associated to each extra signal read and component substituted. The proposal has been validated in a system taken from a real scenario obtained in collaboration with the Airbus Defence and Space company. A statistical analysis of the degree of improvement of the troubleshooting process has also been included.

Структура и свойства листов из нового сплава В-1381 системы Al – Mg – Si

The results of the development of a new alloy of the Al – Mg – Si system of the 6xxx series, which received the V-1381 grade, are presented. The influence of the composition and modes of heat treatment on the mechanical and corrosion properties of sheets with a thickness of 1,0 and 3,0 mm, manufactured under the conditions of FSUE “VIAM”, was investigated. Average level of sheet properties: UTS = 410 MPa, YTS = 360 MPa, El = 11.5 %; fatigue crack growth (dl/dN) = 0,59 mm/kcycle at ΔK = 18,6 MPa·m1/2, intergranular corrosion ≤ 0,15 mm, exfoliation corrosion 4 points. It was found that the structure of the sheets is recrystallized, the main strengthening phase is the coherent matrix β’(Mg2Si)-phase evenly distributed in the volume of grains with a high density. There is also a heterogeneous origin of β′-phase on dislocations and dispersoids. At grain boundaries there are zones free from emissions with a width of 15 – 20 nm. Dispersoids of various morphologies are observed in the tested samples. Temperature and heat values of phase transformations in ingots and sheets are determined and established liquidus and solidus points. The sheet weldability was evaluated by automatic argon-arc welding and the critical rate of deformation of the weld metal during crystallization was determined, at which no cracks were formed in it. Laser welding mode has been developed to ensure optimal formation of geometric parameters of the weld.

Single cell human genomic analyses: a way to refine the knowledge of cellular heterogeneity origins in individual subject

Single cell human genomic analyses: a way to refine the knowledge of cellular heterogeneity origins in individual subject

Evaluation of Genetic Divergence Analysis in Tomato (Solanum lycopersicom [Mill] Wettsd)

The present investigation was carried out to estimate the genetic diversityfor11 yield contributing traits among 50 genotypes of tomato (Solanum lycopersicom [Mill.] Wettsd.) during 2017 in Randomized Block Design with three replications. In this context maximum intra cluster distance was recorded within cluster III and inter cluster distance was recorded between cluster I to V III. Cluster III had maximum number of genotypes. Major cluster in divergence analysis contained genotypes of heterogeneous origin, thereby indicating no parallelism between genetic and geographic diversity. Therefore, crosses between members of clusters separated by high inter- cluster distance are likely to produces desirable segregates.

Transcriptomic and proteomic intra-tumor heterogeneity of colorectal cancer varies depending on tumor location within the colorectum.

Intra-tumor heterogeneity (ITH) of colorectal cancer (CRC) complicates molecular tumor classification, such as transcriptional subtyping. Differences in cellular states, biopsy cell composition, and tumor microenvironment may all lead to ITH. Here we analyze ITH at the transcriptomic and proteomic levels to ascertain whether subtype discordance between multiregional biopsies reflects relevant biological ITH or lack of classifier robustness. Further, we study the impact of tumor location on ITH. Multiregional biopsies from stage II and III CRC tumors were analyzed by RNA sequencing (41 biopsies, 14 tumors) and multiplex immune protein analysis (89 biopsies, 29 tumors). CRC subtyping was performed using consensus molecular subtypes (CMS), CRC intrinsic subtypes (CRIS), and TUMOR types. ITH-scores and network maps were defined to determine the origin of heterogeneity. A validation cohort was used with one biopsy per tumor (162 tumors). Overall, inter-tumor transcriptional variation exceeded ITH, and subtyping calls were frequently concordant between multiregional biopsies. Still, some tumors had high transcriptional ITH and were classified discordantly. Subtyping of proximal MSS tumors were discordant for 50% of the tumors, this ITH was related to differences in the microenvironment. Subtyping of distal MSS tumors were less discordant, here the ITH was more cancer-cell related. The subtype discordancy reflected actual molecular ITH within the tumors. The relevance of the subtypes was reflected at protein level where several inflammation markers were significantly increased in immune related transcriptional subtypes, which was verified in an independent cohort (Wilcoxon rank sum test; p<0.05). Unsupervised hierarchical clustering of the protein data identified large ITH at protein level; as the multiregional biopsies clustered together for only 9 out of 29 tumors. Our transcriptomic and proteomic analyses show that the tumor location along the colorectum influence the ITH of CRC, which again influence the concordance of subtyping.

Exosomes: New Advances in the Translational Potential of the “Garbage Bag”

Bidirectional cell-cell communication via paracrine mechanisms involving nano-sized extracellular vesicles have emerged as a predominant mechanism of cellular signaling. Unlike other shedding vesicles of similar size, exosomes selectively package their cargo using defined mechanisms within the cells. Recent research on exosome signaling describes a messenger-recipient cell dichotomy. The heterogeneous origin of exosome populations, although previously described, has as-yet been incompletely characterized using this dichotomy and thus does not currently provide a complete understanding of exosome populations. In this work, we outline the fundamentally bidirectional nature of exosomes and replace this dichotomy with a messenger-recipient-effector network formed by repackaging and rerelease events. This network further confounds the determination of messenger cell identity among an already heterogeneous exosome population and has major implications for future clinical application. Redefining the axiom of exosome signaling provides a route for future research to consider a multi-system-based approach and underscores a need for enhanced identification methods. This shift also has implications for the use of exosomes as therapeutic agents. Exosome biogenesis and its manipulation will be crucial for the development of curative endogenous exosomes and their synthetic, exogenously produced counterparts. Directed cargo loading, optimal shell composition, and robust production platforms are just some of the design aspects that need to be considered. As tissue-specific therapeutic agents, exosome design will also need to incorporate repackaging mechanics to prevent off-target effects and increase efficacy. A comprehensive current understanding of exosome biogenesis mechanisms amidst the heterogenous EV population will propel the field towards clinical viability.

EPEN-21. IMPAIRED NEURONAL-GLIAL FATE SPECIFICATION IN PEDIATRIC EPENDYMOMA REVEALED BY SINGLE-CELL RNA-SEQ

Ependymoma represents a heterogeneous disease affecting the entire neuraxis. Extensive molecular profiling efforts have identified molecular ependymoma subgroups based on DNA methylation. However, the intratumoral heterogeneity and developmental origins of these groups are only partially understood, and effective treatments are still lacking for about 50% of patients with high-risk tumors. We interrogated the cellular architecture of ependymoma using single cell/nucleus RNA-sequencing to analyze 24 tumor specimens across major molecular subgroups and anatomic locations. We additionally analyzed ten patient-derived ependymoma cell models and two patient-derived xenografts (PDXs). Interestingly, we identified an analogous cellular hierarchy across all ependymoma groups, originating from undifferentiated neural stem cell-like populations towards different degrees of impaired differentiation states comprising neuronal precursor-like, astro-glial-like, and ependymal-like tumor cells. While prognostically favorable ependymoma groups predominantly harbored differentiated cell populations, aggressive groups were enriched for undifferentiated subpopulations. Projection of transcriptomic signatures onto an independent bulk RNA-seq cohort stratified patient survival even within known molecular groups, thus refining the prognostic power of DNA methylation-based profiling. Furthermore, we identified novel potentially druggable targets including IGF- and FGF-signaling within poorly prognostic transcriptional programs. Ependymoma-derived cell models/PDXs widely recapitulated the transcriptional programs identified within fresh tumors and are leveraged to validate identified target genes in functional follow-up analyses. Taken together, our analyses reveal a developmental hierarchy and transcriptomic context underlying the biologically and clinically distinct behavior of ependymoma groups. The newly characterized cellular states and underlying regulatory networks could serve as basis for future therapeutic target identification and reveal biomarkers for clinical trials.

ETMR-06. DISSECTING THE MOLECULAR AND DEVELOPMENTAL BASIS OF PINEOBLASTOMA THROUGH GENOMICS

Pineoblastoma (PB) is an aggressive embryonal brain tumor comprising 1% of pediatric CNS tumors. The clinico-molecular heterogeneity and developmental origins underlying PB are poorly understood; therefore, we have assembled a molecular cohort of histologically defined PBs (n=43) with corresponding outcome data. Methylation profiling revealed four molecularly and clinically distinct PB subgroups, including two novel entities. Mutational and transcriptional analysis identified characteristic molecular features of each subgroup, such as mutations in the miRNA processing pathway or FOXR2 proto-oncogene overexpression. Furthermore, subgroups exhibited differences in propensity for metastasis, cytogenetics, and clinical outcomes. To dissect PB developmental origins and resolve PB subgroup biology, we have employed a combination of single-cell genomics and genetically engineered mouse modeling. We created a single-cell transcriptional atlas of the developing murine pineal gland across 11 timepoints and are currently integrating these data with single nuclei RNA-seq data of human PB (n=25). Single-cell analysis of the developing pineal gland revealed three distinct populations of pinealocytes, referred to as early, mid and late pinealocytes, which segregate by developmental stage yet lie along a single developmental trajectory. Preliminary results implicate significant associations between PBs and the early pinealocyte population as well as subgroup-specific differences in intratumoral heterogeneity. Furthermore, this knowledge has informed the downstream generation of biologically faithful disease models, including a transgenic mouse model of the PB-RB subgroup. Remarkably, this model shows up-regulation of key markers of PB such as Crx, Asmt and Otx2 and substantiates early pinealocytes as the probable cell-of-origin for this PB subgroup.

Integration of spatial and non-spatial information by heterogeneous dentate gyrus granule cells

The hippocampus is the key site for learning and memory and for processing of spatial information in the brain. It is divided into three main subregions: the dentate gyrus (DG), the CA3 area, and the CA1 region, which are linearly interconnected to form a so-called trisynaptic circuit. Thus, the DG sits in a strategic position to gate the flow of information from the neocortex into the hippocampal network. The granule cells (GCs), the main cell type in the DG, receive 'where' and 'what' information from the medial and lateral entorhinal cortex, respectively. How they process this mixed information remains enigmatic. By characterizing the spatial information encoded by the excitatory postsynaptic potentials (EPSPs) in GCs, we demonstrated that the majority of GCs received spatially tuned synaptic input. However, only a minority of GCs successfully converted spatially tuned input to spatially tuned output. Furthermore, we found that mature GCs were highly heterogeneous in terms of their dendritic morphology and intrinsic excitability, which contributes to the sparse and heterogeneous firing of GCs. Finally, we discuss the possible origin of this neural heterogeneity and its potential role in enlarging the computational power of the DG, facilitating pattern separation in this network.

Safety and Efficacy of Bleb Needling with Antimetabolite after Trabeculectomy Failure in Glaucoma Patients: A Systemic Review and Meta-Analysis.

Background Bleb needling with subconjunctival injection of antimetabolites had become a widely accepted approach for trabeculectomy failure. However, IOP reduction effects, success rates, and complications occurrence for this procedure showed great inconsistency among the different studies. Methods We conducted a literature search on PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. A random-effects model was performed on the extracted data based on the included studies. The intraocular pressure (IOP) and number of antiglaucomatous medications before and after the surgery were pooled for meta-analysis. The success and complication rates were estimated based on the results. Subgroup analysis, sensitivity analysis, and metaregression were applied to explore the origination of heterogeneity. Results Thirty-seven studies with a total of 2182 patients were finally included in our review. For the present meta-analysis, the overall effects of bleb needling at the last visit revealed a reduction in IOP of 9.74 mmHg (95% confidence interval (CI) [8.85, 10.63]), 45.9% (95% CI [39.0%, 53.0%]) for complete success rate, and 70.4% (95% CI [63.5%, 77.0%]) for qualified success rate. Application of mitomycin C (MMC) and 5-fluorouracil (5-Fu) during the procedure were efficacious for IOP control during the follow-up. Metaregression revealed that possible origination of heterogeneity was baseline IOP before bleb needling, revealing a trend that higher baseline IOP correlated with a greater IOP reduction results (p < 0.001). For safety profile, conjunctival haemorrhage (5.7%, 95% CI [2.5%, 10.1%]), hyphema (5.5%, 95% CI [3.0%, 8.7%]), and bleb leakage (5.0%, 95% CI [3.2%, 7.3%]) had the highest estimate of incidence. An increasing number of needling was the main risk factor for needling failure. Conclusion Bleb needling with antimetabolites could be considered an effective and safe procedure after trabeculectomy failure. After the process, patients will gain IOP control and reduce antiglaucomatous medications for at least six months with 5-Fu or MMC. Meanwhile, the overall estimates for complications were relatively low in the whole process.

Revealing Solvent Effects on Ion Insertion within Battery Primary Particles Using Operando Scanning Transmission X-Ray Microscopy

LiFePO4 (LFP), the attractive commercial cathode materials, exhibits the phase separation between lithium-poor and lithium-rich phase within individual particles due to the wide miscibility gap. The boundaries between such phases develop large stress, lead to cracks within individual particles, and decay the cycle life. There have been lots of interest in investigating the origin of lithium heterogeneity and manipulating the phase boundaries within the particles during cycling. Previously, we revealed that insertion kinetics is dependent on the local lithium composition from which the hysteresis of lithium spatiodynamics originate. [ref.1] In addition, uniformity of ion insertion kinetics at electrolyte-electrode interface governs lithium heterogeneity and spatiodynamics in ether-based organic electrolyte. [ref.1] However, it remains still unclear how the chemical interaction of lithium ions, electrolyte molecules, and solid electrode controls nanoscale ion insertion kinetics. By developing operando scanning transmission x-ray microscopy (STXM) platform which maps lithium composition within individual LFP particles at 50 nm resolution during cycling, we investigated the interfacial lithium transport in various electrolytes: water, carbonates, and ethers. We synthesized LFP particles with platelet morphology and [010] crystallographic axis, which is fast ion diffusion direction, lied parallel to the monochromatic X-ray allowing to visualize lithium transport in the particles. Herein, we discover that aqueous electrolyte greatly accelerates lithium insertion kinetics, completely redirecting lithium heterogenesity and spatiodynamics compared with organic-based electrolyte. Aqueous environment kinetics show higher exchange current density (~700 mAm-2) than organic EC/DMC (~200 mAm-2) and also higher surface diffusion rate which account for the higher degree of intraparticle phase separation within the particles. By extracting kinetics parameters from our result, we experimentally demonstrate that heterogeneity and spatiodynamics in the single particle kinetics is determined by the strong interaction between the electrolyte molecules and the surface of electrode particles.Ref. 1 J. Lim et al. Science (2016) 353 p566 Figure 1

Self-generated persistent random forces drive phase separation in growing tumors.

A single solid tumor, composed of nearly identical cells, exhibits heterogeneous dynamics. Dynamics of cells in the core is glass-like, whereas those in the periphery undergoes diffusive or super-diffusive behavior. Quantification of heterogeneity using the mean square displacement or the self-intermediate scattering function, which involves averaging over the cell population, hides the complexity of the collective movement. Using the t-distributed stochastic neighbor embedding (t-SNE), a popular unsupervised machine learning dimensionality reduction technique, we show that the phase space structure of an evolving colony of cells, driven by cell division and apoptosis, partitions into nearly disjoint sets composed principally of the core and periphery cells. The non-equilibrium phase separation is driven by the differences in the persistence of self-generated active forces induced by cell division. Extensive heterogeneity revealed by t-SNE paves the way toward understanding the origins of intratumor heterogeneity using experimental imaging data.

Intellectual disability: dendritic anomalies and emerging genetic perspectives.

Intellectual disability (ID) corresponds to several neurodevelopmental disorders of heterogeneous origin in which cognitive deficits are commonly associated with abnormalities of dendrites and dendritic spines. These histological changes in the brain serve as a proxy for underlying deficits in neuronal network connectivity, mostly a result of genetic factors. Historically, chromosomal abnormalities have been reported by conventional karyotyping, targeted fluorescence in situ hybridization (FISH), and chromosomal microarray analysis. More recently, cytogenomic mapping, whole-exome sequencing, and bioinformatic mining have led to the identification of novel candidate genes, including genes involved in neuritogenesis, dendrite maintenance, and synaptic plasticity. Greater understanding of the roles of these putative ID genes and their functional interactions might boost investigations into determining the plausible link between cellular and behavioral alterations as well as the mechanisms contributing to the cognitive impairment observed in ID. Genetic data combined with histological abnormalities, clinical presentation, and transgenic animal models provide support for the primacy of dysregulation in dendrite structure and function as the basis for the cognitive deficits observed in ID. In this review, we highlight the importance of dendrite pathophysiology in the etiologies of four prototypical ID syndromes, namely Down Syndrome (DS), Rett Syndrome (RTT), Digeorge Syndrome (DGS) and Fragile X Syndrome (FXS). Clinical characteristics of ID have also been reported in individuals with deletions in the long arm of chromosome 10 (the q26.2/q26.3), a region containing the gene for the collapsin response mediator protein 3 (CRMP3), also known as dihydropyrimidinase-related protein-4 (DRP-4, DPYSL4), which is involved in dendritogenesis. Following a discussion of clinical and genetic findings in these syndromes and their preclinical animal models, we lionize CRMP3/DPYSL4 as a novel candidate gene for ID that may be ripe for therapeutic intervention.

Sr–Nd–Pb–Hf Isotopic Constraints on the Mantle Heterogeneities beneath the South Mid-Atlantic Ridge at 18–21°S

In an attempt to investigate the nature and origin of mantle heterogeneities beneath the South Mid-Atlantic Ridge (SMAR), we report new whole-rock Sr, Nd, Pb, and Hf isotopic data from eight basalt samples at four dredge stations along the SMAR between 18°S and 21°S. Sr, Nd, and Pb isotopic data from SMAR mid-ocean ridge basalts (MORBs) at 18–21°S published by other researchers were also utilized in this study. The SMAR MORBs at 18–21°S feature the following ratio ranges: 87Sr/86Sr = 0.70212 to 0.70410, 143Nd/144Nd = 0.512893 to 0.513177, 206Pb/204Pb = 18.05 to 19.50, 207Pb/204Pb = 15.47 to 15.71, 208Pb/204Pb = 37.87 to 38.64, and 176Hf/177Hf = 0.283001 to 0.283175. The 87Sr/86Sr, 143Nd/144Nd, 206Pb/204Pb, and 176Hf/177Hf ratios of these MORBs varied considerably along the SMAR axis. The variable compositions of the Sr–Nd–Pb–Hf isotopes, combined with the corresponding whole-rock major and trace elemental abundances reported in previous studies, suggest that the SMAR MORBs at 18–21°S were probably derived from a heterogeneous mantle substrate related to a mixture of depleted mantle (DM) materials with a small amount (but variable input) of HIMU (high-μ, where μ = 238U/204Pb)- and enriched (EMII)-type materials. The HIMU-type materials likely originated from the proximal St. Helena plume and may have been transported through “pipe-like inclined sublithospheric channels” into the SMAR axial zone. The EMII-type materials possibly originated from a recycled metasomatized oceanic crust that may have been derived from the early dispersion of other plume heads into the subcontinental asthenosphere prior to the opening of the South Atlantic Ocean. In addition, the contributions of subducted sediments, continental crust, and subcontinental lithospheric mantle components to the formation of the SMAR MORBs at 18–21°S may be nonexistent or negligible.