Molecular Plasticity Research Articles

Phosphorylation refines the control of complex formation in IDPs.

Dynamic and multivalent interactions are hallmarks of intrinsically disordered proteins (IDPs) acting within complex cellular regulatory pathways. Thanks to their astonishing molecular plasticity, IDPs often interact with numerous binding partners. While the interaction networks are expected to be highly regulated, disentangling the underlying regulatory mechanisms remains challenging. The nuclear coactivator binding domain (NCBD) is a known transcriptional hub in regulatory networks. At equilibrium, two conformations of NCBD exist due to the cis/trans isomerization of a single proline residue: an effect previously shown to expand the tunability of complex formation with the activator for thyroid hormone (ACTR) by orders of magnitude. Interestingly, proline residues are often located, as in the case of NCBD, within phosphorylation motifs.

Effects of Exercise Training on the Phosphoproteomics of the Medial Prefrontal Cortex in Rats With Autism Spectrum Disorder Induced by Valproic Acid

Background The key neural pathological characteristics of autism spectrum disorder (ASD) include abnormal synaptic plasticity of the medial prefrontal cortex (mPFC). Exercise therapy is widely used to rehabilitate children with ASD, but its neurobiological mechanism is unclear. Methods To clarify whether the structural and molecular plasticity of synapses in the mPFC are related to improvement in ASD behavioral deficits after continuous exercise rehabilitation training, we applied phosphoproteomic, behavioral, morphological, and molecular biological methods to investigate the impact of exercise on the phosphoprotein expression profile and synaptic structure of the mPFC in valproic acid (VPA)-induced ASD rats. Results Exercise training differentially regulated the density, morphology, and ultrastructure of synapses in mPFC subregions in the VPA-induced ASD rats. In total, 1031 phosphopeptides were upregulated and 782 phosphopeptides were downregulated in the mPFC in the ASD group. After exercise training, 323 phosphopeptides were upregulated, and 1098 phosphopeptides were downregulated in the ASDE group. Interestingly, 101 upregulated and 33 downregulated phosphoproteins in the ASD group were reversed after exercise training, and these phosphoproteins were mostly involved in synapses. Consistent with the phosphoproteomics data, the total and phosphorylated levels of the proteins MARK1 and MYH10 were upregulated in the ASD group and reversed after exercise training. Conclusions The differential structural plasticity of synapses in mPFC subregions may be the basic neural architecture of ASD behavioral abnormalities. The phosphoproteins involved in mPFC synapses, such as MARK1 and MYH10, may play important roles in the exercise rehabilitation effect on ASD-induced behavioral deficits and synaptic structural plasticity, which requires further investigation.

Molecular plasticity of CBM3 ancillary domain leads to conformational changes in the cellulose binding interface

Carbohydrate-binding modules (CBMs) constitute independently folded domains typically associated with carbohydrate-active enzymes (CAZymes). These modules are considered to have a rigid structure without notable conformational changes upon ligand binding, exhibiting a complementary topography in relation to the target carbohydrate. Herein, the high-resolution SAD-solved structure of a CBM from family 3 (BsCBM3) that binds to crystalline cellulose is reported in two crystalline forms. This module showed molecular plasticity with structural differences detected between the two crystalline forms and high RMSD values when compared to NMR ensemble of models. Pronounced structural variances were observed in the cellulose binding interface between NMR and XTAL structures, which were corroborated by molecular dynamics simulations. These findings support that family 3 CBMs targeting to cellulose are rather structurally dynamic modules than rigid entities, suggesting a potential role of conformational changes in polysaccharide recognition and modulation of enzyme activity.

Large barocaloric effects in two novel ferroelectric molecular plastic crystals

A new type of materials combining a high-temperature plastic phase and a low-temperature ferroelectric phase, the ferroelectric plastic crystals, are promising for application in refrigeration systems based on solid-state caloric effects.

The Influence of Plasticizers and Accelerated Ageing on Biodegradation of PLA under Controlled Composting Conditions

The overall performance of plasticizers on common mechanical and physical properties, as well as on the processability of polylactic acid (PLA) films, is well-explored. However, the influence of plasticizers on biodegradation is still in its infancy. In this study, the influence of natural-based dicarboxylic acid-based ester plasticizers (MC2178 and MC2192), acetyl tributyl citrate (ATBC Citroflex A4), and polyethylene glycol (PEG 400) on the biodegradation of extruded PLA films was evaluated. Furthermore, the influence of accelerated ageing on the performance properties and biodegradation of films was further investigated. The biodegradation of films was determined under controlled thermophilic composting conditions (ISO 14855-1). Apart from respirometry, an evaluation of the degree of disintegration, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM) of film surfaces was conducted. The influence of melt-processing with plasticizers has a significant effect on structural changes. Especially, the degree of crystallinity has been found to be a major factor which affects the biodegradation rate. The lowest biodegradation rates have been evaluated for films plasticized with PEG 400. These lower molecular weight plasticizers enhanced the crystallinity degrees of the PLA phase due to an increase in chain mobility. On the contrary, the highest biodegradation rate was found for films plasticized with MC2192, which has a higher molecular weight and evoked minimal structural changes of the PLA. From the evaluated results, it could also be stated that migration of plasticizers, physical ageing, and chain scission of films prompted by ageing significantly influenced both the mechanical and thermal properties, as well as the biodegradation rate. Therefore, the ageing of parts has to be taken into consideration for the proper evolution of the biodegradation of plasticized PLA and their applications.

Hippocampal Changes Elicited by Metabolic and Inflammatory Stressors following Prenatal Maternal Infection.

The hippocampus participates in spatial navigation and behavioral processes, displays molecular plasticity in response to environmental challenges, and can play a role in neuropsychiatric diseases. The combined effects of inflammatory prenatal and postnatal challenges can disrupt the hippocampal gene networks and regulatory mechanisms. Using a proven pig model of viral maternal immune activation (MIA) matched to controls and an RNA-sequencing approach, the hippocampal transcriptome was profiled on two-month-old female and male offspring assigned to fasting, mimetic viral, or saline treatments. More than 2600 genes presented single or combined effects (FDR-adjusted p-value < 0.05) of MIA, postnatal stress, or sex. Biological processes and pathways encompassing messenger cyclic adenosine 3',5'-monophosphate (cAMP) signaling were enriched with genes including gastric inhibitory polypeptide receptor (GIPR) predominantly over-expressed in the MIA-exposed fasting males relative to groups that differed in sex, prenatal or postnatal challenge. While this pattern was amplified in fasting offspring, the postnatal inflammatory challenge appeared to cancel out the effects of the prenatal challenge. The transcription factors C-terminal binding protein 2 (CTBP2), RE1 silencing transcription factor (REST), signal transducer and activator of transcription 1 (STAT1), and SUZ12 polycomb repressive complex 2 subunit were over-represented among the genes impacted by the prenatal and postnatal factors studied. Our results indicate that one environmental challenge can influence the effect of another challenge on the hippocampal transcriptome. These findings can assist in the identification of molecular targets to ameliorate the effects of pre-and post-natal stressors on hippocampal-associated physiology and behavior.

The architecture of the 10-23 DNAzyme and its implications for DNA-mediated catalysis.

Understanding the molecular features of catalytically active DNA sequences, so-called DNAzymes, is essential not only for our understanding of the fundamental properties of catalytic nucleic acids in general, but may well be the key to unravelling their full potential via tailored modifications. Our recent findings contributed to the endeavour to assemble a mechanistic picture of DNA-mediated catalysis by providing high-resolution structural insights into the 10-23 DNAzyme (Dz) and exposing a complex interplay between the Dz's unique molecular architecture, conformational plasticity, and dynamic modulation by metal ions as central elements of the DNA catalyst. Here, we discuss key features of our findings and compare them to other studies on similar systems.

Single-Cell Transcriptomics Reveals Similarity of Aggressive Infant Acute Lymphoblastic Leukemia Cells to Early Hematopoietic Progenitors

Introduction: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. While the prognosis for children diagnosed with ALL has significantly improved in recent decades, the outlook for infants (under 12 months of age) with ALL remains bleak. In particular, patients with a rearrangement in the KMT2A gene (KMT2A-r) frequently relapse and have low event-free survival. Recent work shows that cancer cells from infant ALL patients with KMT2A-r show a high degree of transcriptional similarity to early lymphocyte precursors (ELPs), suggesting a molecular plasticity that may drive the aggressiveness of this cancer. In this study, we extend these findings to patients with germline KMT2A (KMT2A-g) and assess the predictive value of the ELP signature. Methods: 10x Genomics single-cell Multiome (v1 chemistry) sequencing was performed to generate RNA sequencing (scRNAseq) data for samples collected at diagnosis and remission from 34 patients presenting with ALL at < 12 months of age - 25 KMT2A-r patients and 9 KMT2A-g patients. KMT2A-r patients had either KMT2A-AFF1 (n = 12) or KMT2A-MLLT1 (n = 13) fusions. 19/25 KMT2A-r patients and 0/9 KMT2A-g patients subsequently relapsed. Sequencing data were aligned to GRCh38 and counted using cellranger-6.0.1, with downstream analysis performed using Seurat 4.0.2 in R 4.0.3. A logistic regression model from Khabirova et al., 2022, fit on published scRNAseq data from fetal bone marrow cells (Jardine et al., 2021), was subsequently tested on sequencing data to produce similarity scores for each infant ALL cell to cell types along the hematopoietic developmental trajectory. Results: Our findings confirm that cells from infant ALL patients with KMT2A-r show a high degree of transcriptional similarity to ELPs (Figure A). We find that this holds true at diagnosis (DX) regardless of whether the patients later relapsed or not. Moreover, we observe that in KMT2A-g infant ALL patients, cells show a lower degree of similarity to ELPs than their KMT2A-r counterparts, but nonetheless show a greater similarity to ELPs than other hematopoietic cells. We do not observe a high degree of similarity to ELPs at remission (MD) in any patient group, supporting the idea that it is leukemic blasts that are similar to ELPs. Strikingly, we also observe that among KMT2A-r patients, a higher proportion of cells highly similar to ELPs is not predictive of subsequent relapse (Figure B). Conclusions: Here we confirm that KMT2A-r infant ALL cancer cells are transcriptionally similar to ELPs, highly plastic hematopoietic progenitors. This plasticity may play a significant role in the aggressiveness of this cancer. We show that this similarity does not exist to the same extent in KMT2A-g patients, consistent with their better prognosis. Additionally, we demonstrate that proportion of ELP-like cells is not predictive of relapse among KMT2A-r patients, suggesting that more work is needed to better understand the significance of similarity to ELPs in this disease. Deeper investigation of gene expression in ELP-like leukemic blasts will shed further light on the molecular mechanisms of this cancer and facilitate improved treatment selection and development of novel therapies for infants with ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TMIC-40. TRANSCRIPTOMIC CHARACTERIZATION OF PATIENT GLIOMAS AND DERIVED MODEL SYSTEMS REVEALS ENVIRONMENTAL INFLUENCE ON NEURODEVELOPMENTAL CELLULAR STATES

Abstract Bulk tumor and single-cell RNA sequencing have revealed the remarkable molecular heterogeneity and plasticity of gliomas, leading to the definition of tumor subtypes and cellular states describing inter- and intra-tumoral levels of heterogeneity respectively. While there has been great interest in creating and revising these classifications, the combination of selective pressures from molecular alterations within the tumor cell as well as extrinsic factors within the tumor microenvironment (TME) driving these levels of heterogeneity remain to be fully described. The brain TME is a complex, regionally heterogeneous ecosystem of communicating non-malignant and malignant cell types and scavenge-able nutrients and metabolites. We hypothesized that distinct environmental contexts within and across tumors may drive the intra- and inter-tumoral heterogeneity of gliomas. To identify tumorigenic programs impacted by environmental context, we performed bulk RNA sequencing of over 40 triplets of patient glioma samples and their matched derivative models established in direct orthotopic mouse xenografts and conventional gliomasphere cultures. Comparative analyses revealed environment-associated programs including in vivo immune and neuroglial signaling as well as altered in vitro lipid metabolism and upregulated cell migration. Next, to investigate associations between tumor cellular state and environment-associated programs we performed single-cell RNA sequencing of 4 patient and model system triplets. By annotating single cell profiles with previously defined single cell atlases of the developing and adult brain, 9 major states reflecting neurodevelopmental cell types were identified. Single cell profiling further revealed cell state-specific expression of environment-associated programs. We simultaneously observed the divergence of model cellular state compositions towards states expressing programs associated with their environment. We conclude that the transcriptional evolution of cellular states is connected to their ecological role within the TME. Consequently, we find grade- and diagnosis-associated composition differences between patient tumors predictive of their ability to establish a model in vitro.

Population specific methylome remodeling in high and low elevation populations of Indian west Himalayan Arabidopsis thaliana in response to elevated CO2

Unravelling the plants responses towards rising atmospheric [CO 2 ] have largely been explored in genetical and morpho-physiological contexts. However, epigenetic factors including DNA methylation which play critical roles in adaptation are largely unexplored. Here we investigated the methylome, transcriptome and morpho-physiological responses of the two Arabidopsis thaliana populations evolved at high (3400 m amsl) and low elevation (700 m amsl) zones to elevated [CO 2 ] (e[CO 2 ]). We show that depending on the origin of the population, there were local level variations in DNA methylation when exposed to e[CO 2 ], but global methyl cytosine (mC) content remained unchanged. Further, there was loss of methylation and more protein coding genes were differentially methylated than transposable elements and non-coding RNA genes, in both the populations but more so in the low elevation one. The differentially methylated genes of the two populations belonged to distinct functional categories. More genes related to methylation machinery were down-regulated in the high elevation population than the low elevation one. Although there was no correlation between methylation and gene expression at the global scale but a few genes exhibited methylation dependent expression level. Finally the hyper- and hypo-methylated status of a few genes due to e[CO 2 ] treatment were validated. Overall, our data suggested the two populations responded differently towards e[CO 2 ] with respect to methylome remodeling, phenotypic and molecular plasticity. However, methylome remodeling and molecular plasticity were more prominent in the low elevation population. Understanding the evolution of epigenetic response towards e[CO 2 ] may help in future crop improvement strategies. • Elevated CO 2 affects DNA methylation remodeling in Arabidopsis thaliana depending on origin of the population. • Methylome remodeling and molecular plasticity of the low elevation population were more than the higher elevation one. • More protein coding genes were differentially methylated in response to elevated CO 2. • Elevated CO 2 induced global gene expression and methylation is not co-linear.

The augmin complex architecture reveals structural insights into microtubule branching.

In mitosis, the augmin complex binds to spindle microtubules to recruit the γ-tubulin ring complex (γ-TuRC), the principal microtubule nucleator, for the formation of branched microtubules. Our understanding of augmin-mediated microtubule branching is hampered by the lack of structural information on the augmin complex. Here, we elucidate the molecular architecture and conformational plasticity of the augmin complex using an integrative structural biology approach. The elongated structure of the augmin complex is characterised by extensive coiled-coil segments and comprises two structural elements with distinct but complementary functions in γ-TuRC and microtubule binding, linked by a flexible hinge. The augmin complex is recruited to microtubules via a composite microtubule binding site comprising a positively charged unordered extension and two calponin homology domains. Our study provides the structural basis for augmin function in branched microtubule formation, decisively fostering our understanding of spindle formation in mitosis.

INFLUENCE OF MOISTURE ON THE SHORT-RANGE ORDERING OF CROSSLINKED GLYCOPOLYMERS BASED ON PLANT POLYSACCHARIDE KONJAC GLUCOMANNAN

Using X-ray diffraction data the short-range ordering was analyzed of the plant polysaccharide konjac glucomannan (KGM) and glycopolymers of different composition based on KGM and ε-caprolactam blocked isocyanates in the presence of saturated water vapor both for moistened and dried systems. The decrease in the values of the Breg’s period corresponding to the average distances between atoms and atomic groups in saturated water vapor is shown for glycopolymers placed under normal conditions. It was found that when the crosslinked KGM based glycopolymers are moistened, a secondary maximum is observed on the diffractograms, which corresponds to the ordering of the polysaccharide chains in the transverse direction. This secondary maximum was observed on the diffractograms of uncrosslinked KGM, but was absent on the initial diffractograms of crosslinked samples. This secondary maximum does not appear again on the diffractograms of dried glycopolymer samples. The influence of moisturizing-drying processes on the structuring and moisture content in polysaccharide and glycopolymers is analyzed. The results of WAXS correlate with thermogravimetry data on changes in the ability of KGM and KGM-based glicopolymers to retain moisture in humidified and dried systems. Using a nitroxyl paramagnetic probe, it has been demonstrated that the increase in molecular mobility of glycomolymers based on konjac glucomannan under the influence of low molecular weight plasticizer does not depend on isocyanate used. This effect allows correlating the irreversible effect of swelling and subsequent drying on the characteristics of these KGM-based systems with the achievement of macrochains of the polymer more equilibrium conformations due to increasing molecular mobility in the presence of moisture.

Social stress under binge-like alcohol withdrawal in adolescence: evidence of cannabidiol effect on maladaptive plasticity in rats.

Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), i.e. the neural hub for processing reward and aversive responses. As socially stressful events pose particular challenges at developmental stages, this research applied the resident-intruder paradigm as a model of social stress, to highlight behavioural neuroendocrine and molecular maladaptive plasticity in rats at withdrawal from binge-like alcohol exposure in adolescence. In search of a rescue agent, cannabidiol (CBD) was selected due to its favourable effects on alcohol- and stress-related harms. Binge-like alcohol exposed intruder rats displayed a compromised defensive behaviour against the resident and a blunted response of the stress system, in addition to indexes of abnormal dopamine (DA)/glutamate plasticity and dysfunctional spine dynamics in the NAc. CBD administration (60 mg/kg) was able to: (1) increase social exploration in the binge-like alcohol exposed intruder rats, at the expenses of freezing time, and in control rats, which received less aggressive attacks from the resident; (2) reduce corticosterone levels independently on alcohol previous exposure; (3) restore DA transmission and (4) facilitate excitatory postsynaptic strength and remodelling. Overall, the maladaptive behavioural and synaptic plasticity promoted by the intersection between binge-like alcohol withdrawal and exposure to adverse social stress can be rescued by a CBD détente effect that results in a successful defensive strategy, supported by a functional endocrine and synaptic plasticity. The current data highlight CBD's relevant therapeutic potential in alcohol- and stress-related harms, and prompt further investigation on its molecular targets.

The Brain Protein Atlas: A conglomerate of proteomics datasets of human neural tissue.

The human brain represents one of the most complex biological structures with significant spatiotemporal molecular plasticity occurring through early development, learning, aging, and disease. While much progress has been made in mapping its transcriptional architecture, more downstream phenotypic readouts are relatively scarce due to limitations with tissue heterogeneity and accessibility, as well as an inability to amplify protein species prior to global -OMICS analysis. To address some of these barriers, our group has recently focused on using mass-spectrometry workflows compatible with small amounts of formalin-fixed paraffin-embedded tissue samples. This has enabled exploration into spatiotemporal proteomic signatures of the brain and disease across otherwise inaccessible neurodevelopmental timepoints and anatomical niches. Given the similar theme and approaches, we introduce an integrated online portal, "The Brain Protein Atlas (BPA)" (www.brainproteinatlas.org), representing a public resource that allows users to access and explore these amalgamated datasets. Specifically, this portal contains a growing set of peer-reviewed mass-spectrometry-based proteomic datasets, including spatiotemporal profiles of human cerebral development, diffuse gliomas, clinically aggressive meningiomas, and a detailed anatomic atlas of glioblastoma. One barrier to entry in mass spectrometry-based proteomics data analysis is the steep learning curve required to extract biologically relevant data. BPA, therefore, includes several built-in analytical tools to generate relevant plots (e.g., volcano plots, heatmaps, boxplots, and scatter plots) and evaluate the spatiotemporal patterns of proteins of interest. Future iterations aim to expand available datasets, including those generated by the community at large, and analytical tools for exploration. Ultimately, BPA aims to improve knowledge dissemination of proteomic information across the neuroscience community in hopes of accelerating the biological understanding of the brain and various maladies.

Design and Synthesis of Epoxidized Soybean Oil‐Branched Cardanol Ethers as Poly(vinyl chloride) Plasticizers

AbstractTo overcome the migration of epoxidized soybean oil (ESO) used as a poly(vinyl chloride) (PVC) plasticizer, ESO‐branched cardanol (CD) ethers (ESO‐CDn) are designed and synthesized in this work. The incorporation of the benzene ring and the C15 straight chain of CD provided excellent plasticizing efficiency, and the increase in the molecular weight by branching CD with ESO enhanced the migration resistance of the plasticizer. In this work, two different methods are adopted to prepare PVC/ESO/CD and PVC/ESO‐CDn, namely the one‐step method (dynamic vulcanization of ESO, CD, and PVC) and the two‐step method (synthesis of ESO‐CD and then mixing it with PVC). The first method is convenient, while it is also uncontrollable, leading to an incomplete reaction between ESO and CD. The second method offers a controllable reaction between ESO and CD. The chemical structure of ESO‐CDn is fully characterized. Furthermore, the thermal, mechanical, rheology, and migration resistance properties of PVC/ESO/CD and PVC/ESO‐CDn are compared. The relationship between the molecular structure and plasticizer performance is investigated, and the plasticization mechanism is proposed. The tensile and thermal properties indicate that PVC/35ESO‐CD10 offered a superior anti‐thermal aging performance due to the excellent plasticizing and migration resistance effects of ESO‐CD10.

Molecular plasticity to soil water deficit differs between sessile oak (Quercus Petraea (Matt.) Liebl.) high- and low-water use efficiency genotypes.

Water use efficiency (WUE) is an important adaptive trait for soil water deficit. The molecular and physiological bases of WUE regulation in crops have been studied in detail in the context of plant breeding. Knowledge for most forest tree species lags behind, despite the need to identify populations or genotypes able to cope with the longer, more intense drought periods likely to result from climate warming. We aimed to bridge this gap in knowledge for sessile oak (Quercus petraea (Matt.) Liebl.), one of the most ecologically and economically important tree species in Europe, using a factorial design including trees with contrasted phenotypic values (low and high WUE) and two watering regimes (control and drought). By monitoring the ecophysiological response, we first qualified genotypes for their WUE (by using instantaneous and long-term measures). We then performed RNA-seq to quantify gene expression for the three most extreme genotypes exposed to the two watering regimes. By analyzing the interaction term, we were able to capture the molecular strategy of each group of plants for coping with drought. We identified putative candidate genes potentially involved in the regulation of transpiration rate in high-WUE phenotypes. Regardless of water availability, trees from the high-WUE phenotypic class overexpressed genes associated with drought responses, and in the control of stomatal density and distribution, and displayed a downregulation of genes associated with early stomatal closure and high transpiration rate. Fine physiological screening of sessile oaks with contrasting WUE, and their molecular characterization (i) highlighted subtle differences in transcription between low- and high-WUE genotypes, identifying key molecular players in the genetic control of this trait and (ii) revealed the genes underlying the molecular strategy that evolved in each group to potentially cope with water deficit, providing new insight into the within-species diversity in drought adaptation strategies.

Molecular plasticity to soil water deficit differs between sessile oak (Quercus Petraea (Matt.) Liebl.) high- and low-water use efficiency genotypes.

Molecular plasticity to soil water deficit differs between sessile oak (Quercus Petraea (Matt.) Liebl.) high- and low-water use efficiency genotypes.

Evidence for close molecular proximity between reverting and undifferentiated cells

BackgroundAccording to Waddington’s epigenetic landscape concept, the differentiation process can be illustrated by a cell akin to a ball rolling down from the top of a hill (proliferation state) and crossing furrows before stopping in basins or “attractor states” to reach its stable differentiated state. However, it is now clear that some committed cells can retain a certain degree of plasticity and reacquire phenotypical characteristics of a more pluripotent cell state. In line with this dynamic model, we have previously shown that differentiating cells (chicken erythrocytic progenitors (T2EC)) retain for 24 h the ability to self-renew when transferred back in self-renewal conditions. Despite those intriguing and promising results, the underlying molecular state of those “reverting” cells remains unexplored. The aim of the present study was therefore to molecularly characterize the T2EC reversion process by combining advanced statistical tools to make the most of single-cell transcriptomic data. For this purpose, T2EC, initially maintained in a self-renewal medium (0H), were induced to differentiate for 24H (24H differentiating cells); then, a part of these cells was transferred back to the self-renewal medium (48H reverting cells) and the other part was maintained in the differentiation medium for another 24H (48H differentiating cells). For each time point, cell transcriptomes were generated using scRT-qPCR and scRNAseq.ResultsOur results showed a strong overlap between 0H and 48H reverting cells when applying dimensional reduction. Moreover, the statistical comparison of cell distributions and differential expression analysis indicated no significant differences between these two cell groups. Interestingly, gene pattern distributions highlighted that, while 48H reverting cells have gene expression pattern more similar to 0H cells, they are not completely identical, which suggest that for some genes a longer delay may be required for the cells to fully recover. Finally, sparse PLS (sparse partial least square) analysis showed that only the expression of 3 genes discriminates 48H reverting and 0H cells.ConclusionsAltogether, we show that reverting cells return to an earlier molecular state almost identical to undifferentiated cells and demonstrate a previously undocumented physiological and molecular plasticity during the differentiation process, which most likely results from the dynamic behavior of the underlying molecular network.

Effect of Plasticization on Stretching Stability of Poly(Vinyl Alcohol) Films: A Case Study Using Glycerol and Water.

Adding small molecular plasticizers is the most common route to tailor the stretchability of poly(vinyl alcohol) (PVA). However, how the plasticization along with the nature of the plasticizer governs the structural homogeneity during stretching remains an open question to answer. Herein, two representative plasticizers, glycerol (GLY) and water, are chosen to endow the PVA films with ductility. It is found that large strain cavitations cause obvious stress whitening in the PVA/H2 O films; on the contrary, most of the PVA/GLY films maintain transparent undergoing tensile deformation. Through a combination of experimental inspections and molecular dynamic simulation, it is revealed that partial water molecules that behave as free water will aggregate into microdomains, which serve as mechanical defects responsible for yielding voids. Whereas, the GLY plasticizer homogeneously disperses at a molecular level and interacts with PVA chains through strong hydrogen bonds. More interestingly, it is illustrated that the dispersion and bound states of plasticizers are closely related to the mechanical character of the plasticized PVA films. These findings offer new insight into the working mechanism of plasticization on the structural stability during stretching, and guide the design of PVA/plasticizer system to obtain excellent comprehensive mechanics.

Keeping synapses in shape: degradation pathways in the healthy and aging brain.

Synapses maintain their molecular composition, plasticity and function through the concerted action of protein synthesis and removal. The complex and polarized neuronal architecture poses specific challenges to the logistics of protein and organelle turnover since protein synthesis and degradation mainly happen in the cell soma. In addition, post-mitotic neurons accumulate damage over a lifetime, challenging neuronal degradative pathways and making them particularly susceptible to the effects of aging. This review will summarize the current knowledge on neuronal protein turnover mechanisms with a particular focus on the presynapse, including the proteasome, autophagy and the endolysosomal route and their roles in regulating presynaptic proteostasis and function. In addition, the author will discuss how physiological brain aging, which entails a progressive decline in cognitive functions, affects synapses and the degradative machinery.