Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.

Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

Subtype-specific 3D genome alteration in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) represents a set of heterogeneous myeloid malignancies, and hallmarks include mutations in epigenetic modifiers, transcription factors and kinases1-5. The extent to which mutations in AML drive alterations in chromatin 3D structure and contribute to myeloid transformation is unclear. Here we use Hi-C and whole-genome sequencing to analyse 25 samples from patients with AML and 7 samples from healthy donors. Recurrent and subtype-specific alterations in A/B compartments, topologically associating domains and chromatin loops were identified. RNA sequencing, ATAC with sequencing and CUT&Tag for CTCF, H3K27ac and H3K27me3 in the same AML samples also revealed extensive and recurrent AML-specific promoter-enhancer and promoter-silencer loops. We validated the role of repressive loops on their target genes by CRISPR deletion and interference. Structural variation-induced enhancer-hijacking and silencer-hijacking events were further identified in AML samples. Hijacked enhancers play a part in AML cell growth, as demonstrated by CRISPR screening, whereas hijacked silencers have a downregulating role, as evidenced by CRISPR-interference-mediated de-repression. Finally, whole-genome bisulfite sequencing of 20 AML and normal samples revealed the delicate relationship between DNA methylation, CTCF binding and 3D genome structure. Treatment of AML cells with a DNA hypomethylating agent and triple knockdown of DNMT1, DNMT3A and DNMT3B enabled the manipulation of DNA methylation to revert 3D genome organization and gene expression. Overall, this study provides a resource for leukaemia studies and highlights the role of repressive loops and hijacked cis elements in human diseases.

scQTLbase: an integrated human single-cell eQTL database.

Genome-wide association studies (GWAS) have identified numerous genetic variants associated with diseases and traits. However, the functional interpretation of these variants remains challenging. Expression quantitative trait loci (eQTLs) have been widely used to identify mutations linked to disease, yet they explain only 20-50% of disease-related variants. Single-cell eQTLs (sc-eQTLs) studies provide an immense opportunity to identify new disease risk genes with expanded eQTL scales and transcriptional regulation at a much finer resolution. However, there is no comprehensive database dedicated to single-cell eQTLs that users can use to search, analyse and visualize them. Therefore, we developed the scQTLbase (http://bioinfo.szbl.ac.cn/scQTLbase), the first integrated human sc-eQTLs portal, featuring 304 datasets spanning 57 cell types and 95 cell states. It contains ∼16 million SNPs significantly associated with cell-type/state gene expression and ∼0.69 million disease-associated sc-eQTLs from 3 333 traits/diseases. In addition, scQTLbase offers sc-eQTL search, gene expression visualization in UMAP plots, a genome browser, and colocalization visualization based on the GWAS dataset of interest. scQTLbase provides a one-stop portal for sc-eQTLs that will significantly advance the discovery of disease susceptibility genes.

ipaQTL-atlas: an atlas of intronic polyadenylation quantitative trait loci across human tissues.

Functional interpretation of disease-associated non-coding variants remains a significant challenge in the post-GWAS era. Our recent study has identified 3'UTR alternative polyadenylation (APA) quantitative trait loci (3'aQTLs) and connects APA events with QTLs as a major driver of human traits and diseases. Besides 3'UTR, APA events can also occur in intron regions, and increasing evidence has connected intronic polyadenylation with disease risk. However, systematic investigation of the roles of intronic polyadenylation in human diseases remained challenging due to the lack of a comprehensive database across a variety of human tissues. Here, we developed ipaQTL-atlas (http://bioinfo.szbl.ac.cn/ipaQTL) as the first comprehensive portal for intronic polyadenylation. The ipaQTL-atlas is based on the analysis of 15 170 RNA-seq data from 838 individuals across 49 Genotype-Tissue Expression (GTEx v8) tissues and contains ∼0.98 million SNPs associated with intronic APA events. It provides an interface for ipaQTLs search, genome browser, boxplots, and data download, as well as the visualization of GWAS and ipaQTL colocalization results. ipaQTL-atlas provides a one-stop portal to access intronic polyadenylation information and could significantly advance the discovery of APA-associated disease susceptibility genes.

Farmland Microhabitat Mediated by a Residual Microplastic Film: Microbial Communities and Function.

How the plastisphere mediated by the residual microplastic film in farmlands affects microhabitat systems is unclear. Here, microbial structure, assembly, and biogeochemical cycling in the plastisphere and soil in 33 typical farmland sites were analyzed by amplicon sequencing of 16S rRNA genes and ITS and metagenome analysis. The results indicated that residual microplastic film was colonized by microbes, forming a unique niche called the plastisphere. Notable differences in the microbial community structure and function were observed between soil and plastisphere. Residual microplastic film altered the microbial symbiosis and assembly processes. Stochastic processes significantly dominated the assembly of the bacterial community in the plastisphere and soil but only in the plastisphere for the fungal community. Deterministic processes significantly dominated the assembly of fungal communities only in soil. Moreover, the plastisphere mediated by the residual microplastic film acted as a preferred vector for pathogens and microorganisms associated with plastic degradation and the nitrogen and sulfur cycle. The abundance of genes associated with denitrification and sulfate reduction activity in the plastisphere was pronouncedly higher than that of soil, which increase the potential risk of nitrogen and sulfur loss. The results will offer a scientific understanding of the harm caused by the residual microplastic film in farmlands.

A New Target Detection Method of Ferrography Wear Particle Images Based on ECAM-YOLOv5-BiFPN Network.

For mechanical equipment, the wear particle in the lubrication system during equipment operation can reflect the lubrication condition, wear mechanism, and severity of wear between equipment friction pairs. To solve the problems of false detection and missed detection of small, dense, and overlapping wear particles in the current ferrography wear particle detection model in a complex oil background environment, a new ferrography wear particle detection network, EYBNet, is proposed. Firstly, the MSRCR algorithm is used to enhance the contrast of wear particle images and reduce the interference of complex lubricant backgrounds. Secondly, under the framework of YOLOv5s, the accuracy of network detection is improved by introducing DWConv and the accuracy of the entire network is improved by optimizing the loss function of the detection network. Then, by adding an ECAM to the backbone network of YOLOv5s, the saliency of wear particles in the images is enhanced, and the feature expression ability of wear particles in the detection network is enhanced. Finally, the path aggregation network structure in YOLOv5s is replaced with a weighted BiFPN structure to achieve efficient bidirectional cross-scale connections and weighted feature fusion. The experimental results show that the average accuracy is increased by 4.46%, up to 91.3%, compared with YOLOv5s, and the detection speed is 50.5FPS.

Stachydrine, a Bioactive Equilibrist for Synephrine, Identified from Four Citrus Chinese Herbs.

Four Chinese herbs from the Citrus genus, namely Aurantii Fructus Immaturus (Zhishi), Aurantii Fructus (Zhiqiao), Citri Reticulatae Pericarpium Viride (Qingpi) and Citri Reticulatae Pericarpium (Chenpi), are widely used for treating various cardiovascular and gastrointestinal diseases. Many ingredients have already been identified from these herbs, and their various bioactivities provide some interpretations for the pharmacological functions of these herbs. However, the complex functions of these herbs imply undisclosed cholinergic activity. To discover some ingredients with cholinergic activity and further clarify possible reasons for the complex pharmacological functions presented by these herbs, depending on the extended structure-activity relationships of cholinergic and anti-cholinergic agents, a simple method was established here for quickly discovering possible choline analogs using a specific TLC method, and then stachydrine and choline were first identified from these Citrus herb decoctions based on their NMR and HRMS data. After this, two TLC scanning (TLCS) methods were first established for the quantitative analyses of stachydrine and choline, and the contents of the two ingredients and synephrine in 39 samples were determined using the valid TLCS and HPLC methods, respectively. The results showed that the contents of stachydrine (3.04‱) were 2.4 times greater than those of synephrine (1.25‱) in Zhiqiao and about one-third to two-thirds of those of Zhishi, Qingpi and Chenpi. Simultaneously, the contents of stachydrine, choline and synephrine in these herbs present similar decreasing trends with the delay of harvest time; e.g., those of stachydrine decrease from 5.16‱ (Zhishi) to 3.04‱ (Zhike) and from 1.98‱ (Qingpi) to 1.68‱ (Chenpi). Differently, the contents of synephrine decrease the fastest, while those of stachydrine decrease the slowest. Based on these results, compared with the pharmacological activities and pharmacokinetics reported for stachydrine and synephrine, it is indicated that stachydrine can be considered as a bioactive equilibrist for synephrine, especially in the cardio-cerebrovascular protection from these citrus herbs. Additionally, the results confirmed that stachydrine plays an important role in the pharmacological functions of these citrus herbs, especially in dual-directionally regulating the uterus, and in various beneficial effects on the cardio-cerebrovascular system, kidneys and liver.

A probabilistic Boolean model on hair follicle cell fate regulation by TGF-ß.

Hair follicles (HFs) are mini skin organs that undergo cyclic growth. Various signals regulate HF cell fate decisions jointly. Recent experimental results suggest that transforming growth factor beta (TGF-ß) exhibits a dual role in HF cell fate regulation that can be either anti- or pro-apoptosis. To understand the underlying mechanisms of HF cell fate control, we develop a novel probabilistic Boolean network (pBN) model on the HF epithelial cell gene regulation dynamics. First, the model is derived from literature, then refined using single-cell RNA sequencing data. Using the model, we both explore the mechanisms underlying HF cell fate decisions and make predictions that could potentially guide future experiments: 1) we propose that a threshold-like switch in the TGF-ß strength may necessitate the dual roles of TGF-ß in either activating apoptosis or cell proliferation, in cooperation with bone morphogenetic protein (BMP) and tumor necrosis factor (TNF) and at different stages of a follicle growth cycle; 2) our model shows concordance with the high-activator-low-inhibitor theory of anagen initiation; 3) we predict that TNF may be more effective in catagen initiation than TGF-ß, and they may cooperate in a two-step fashion; 4) finally, predictions of gene knockout and overexpression reveal the roles in HF cell fate regulations of each gene. Attractor and motif analysis from the associated Boolean networks reveal the relations between the topological structure of the gene regulation network and the cell fate regulation mechanism. A discrete spatial model equipped with the pBN illustrates how TGF-ß and TNF cooperate in initiating and driving the apoptosis wave during catagen.

Modeling of ionizing radiation induced hair follicle regenerative dynamics.

Hair follicles (HFs) are stem-cell-rich mammalian mini-organs that can undergo cyclic regenerations over the life span of the organism. The cycle of a HF consists of three consecutive phases: anagen-the active proliferation phase, catagen-the degeneration phase, and telogen-the resting phase. While HFs undergo irreversible degeneration during catagen, recent experimental research on mice shows that when anagen HFs are subject to ionizing radiation (IR), they undergo a transient degeneration, followed by a nearly full regeneration that makes the HFs return to homeostatic state. The mechanisms underlying these IR-induced HF regenerative dynamics and the catagen degenerative dynamics, remain unknown. In this work, we develop an ODE type cell differentiation population model to study the control mechanisms of HF regeneration. The model is built based on current theoretical knowledge in biology and mathematically formulated using feedback mechanisms. Model parameters are calibrated to IR experimental data, and we then provide modeling results with both deterministic ODE simulations and corresponding stochastic simulations. We perform stability and bifurcation analyses on the ODE model, which reveal that for anagen HFs, a low spontaneous apoptosis rate secures the stability of the HF homeostatic steady state, allowing the HF to regenerate even when subject to strong IR. On the other hand, the irreversible degeneration during catagen results from both strong spontaneous apoptosis rate and strong apoptosis feedback. Lastly, we perform sensitivity analysis to identify key parameters in the model to validate these hypotheses.

A multiscale model via single-cell transcriptomics reveals robust patterning mechanisms during early mammalian embryo development.

During early mammalian embryo development, a small number of cells make robust fate decisions at particular spatial locations in a tight time window to form inner cell mass (ICM), and later epiblast (Epi) and primitive endoderm (PE). While recent single-cell transcriptomics data allows scrutinization of heterogeneity of individual cells, consistent spatial and temporal mechanisms the early embryo utilize to robustly form the Epi/PE layers from ICM remain elusive. Here we build a multiscale three-dimensional model for mammalian embryo to recapitulate the observed patterning process from zygote to late blastocyst. By integrating the spatiotemporal information reconstructed from multiple single-cell transcriptomic datasets, the data-informed modeling analysis suggests two major processes critical to the formation of Epi/PE layers: a selective cell-cell adhesion mechanism (via EphA4/EphrinB2) for fate-location coordination and a temporal attenuation mechanism of cell signaling (via Fgf). Spatial imaging data and distinct subsets of single-cell gene expression data are then used to validate the predictions. Together, our study provides a multiscale framework that incorporates single-cell gene expression datasets to analyze gene regulations, cell-cell communications, and physical interactions among cells in complex geometries at single-cell resolution, with direct application to late-stage development of embryogenesis.

Self-sustained three-dimensional beating of a model eukaryotic flagellum.

Flagella and cilia are common features of a wide variety of biological cells and play important roles in locomotion and feeding at the microscale. The beating of flagella is controlled by molecular motors that exert forces along the length of the flagellum and are regulated by a feedback mechanism coupled to the flagella deformation. We develop a three-dimensional (3D) flagellum beating model based on sliding-controlled motor feedback, accounting for both bending and twist, as well as differential bending resistances along and orthogonal to the major bending plane of the flagellum. We show that beating is generated and sustained spontaneously for a sufficiently high motor activity through an instability mechanism. Isotropic bending rigidities in the flagellum lead to 3D helical beating patterns. By contrast, anisotropic flagella present a rich variety of wave-like beating dynamics, including both 3D beating patterns as well as planar beating patterns. We show that the ability to generate nearly planar beating despite the 3D beating machinery requires only a modest degree of bending anisotropy, and is a feature observed in many eukaryotic flagella such as mammalian spermatozoa.

Development and initial validation of the Chinese Version of the Noise Exposure Questionnaire (C-NEQ).

BACKGROUND: With a high prevalence of noise-induced hearing loss (NIHL), the noise survey tools for identifying individuals with high risk of NIHL are still limited. This study was aimed to translate and develop a Chinese version of noise exposure questionnaire (C-NEQ), and validate its reliability and reproducibility. METHODS: This study was conducted from May 2020 to March 2021 in China. The questionnaire was translated from the original NEQ and adapted into Chinese culture using the method according to the International Test Committee. Content validity was evaluated by our expert group. Construct validity and reliability of the C-NEQ was determined through estimating the confirmatory factor analysis and Cronbach's alpha in a cross-sectional analysis among 641 Chinese speaking adults, respectively. The retest reproducibility of the C-NEQ was analyzed by using the intra-group correlation coefficient (ICC) in a follow-up analysis among 151 participants. RESULTS: The C-NEQ comprises ten items covering four domains: occupational, housework, transport and recreational noise exposure. The annual noise exposure (ANE) was calculated as the protocol of original NEQ. A total of 641 adult participants (aged 26.9 ± 10.1 years, 53.4% males) completed the C-NEQ. The average time for completing the C-NEQ was 4.4 ± 3.0 min. Content validity indicated high relevance of the C-NEQ. The confirmatory factor analysis indices illustrated that the items of the C-NEQ were suitable with the data in the study. For the internal reliability, the Cronbach's α coefficients of the total items and four domains (occupational, housework, transport, and recreational noise exposure) were 0.799, 0.959, 0.837, 0.825, and 0.803, respectively. Among them, 151 participants (aged 36.1 ± 11.1 years, 65.6% males) completed the retest of the C-NEQ 1 month after the first test. The ICC value of total ANEs between the first test and the second test was 0.911 (P < 0.001). CONCLUSIONS: In this study, we have validated the C-NEQ with adequate reliability and reproducibility for quantifying an individual's annual daily noise exposure, which provides an effective fast-screen tool for researches and clinics to identify those individuals with high risks of NIHL within the short time duration (no more than five minutes) among Chinese population.

Two new flavonol glycosides from Selaginella tamariscina.

Two new flavonol glycosides 3,5,7-trimethoxyflavone-4'-O-[5'''-O-p-coumaroyl-ß-D-apiofuranoyl-(1'''→2'')-ß-D-glucopyranoside] (1) and 3,5,7-trimethoxyflavone -4'-O-ß-D-glucopyranoside (2) were isolated from Selaginella tamariscina. The structures of 1 and 2 were elucidated on the basis of chemical and spectral analysis, including 1D, 2D NMR analyses and HRESIMS spectrometry. Two compounds were evaluated for cytotoxic activities against A-375, MCF-7, MDA-MB-231 and MDA-MB-468 cell lines by MTT assay. Unfortunately, two compounds displayed no cytotoxic activities.

Identification and characterization of amphibian SLC26A5 using RNA-Seq.

BACKGROUND: Prestin (SLC26A5) is responsible for acute sensitivity and frequency selectivity in the vertebrate auditory system. Limited knowledge of prestin is from experiments using site-directed mutagenesis or domain-swapping techniques after the amino acid residues were identified by comparing the sequence of prestin to those of its paralogs and orthologs. Frog prestin is the only representative in amphibian lineage and the studies of it were quite rare with only one species identified. RESULTS: Here we report a new coding sequence of SLC26A5 for a frog species, Rana catesbeiana (the American bullfrog). In our study, the SLC26A5 gene of Rana has been mapped, sequenced and cloned successively using RNA-Seq. We measured the nonlinear capacitance (NLC) of prestin both in the hair cells of Rana's inner ear and HEK293T cells transfected with this new coding gene. HEK293T cells expressing Rana prestin showed electrophysiological features similar to that of hair cells from its inner ear. Comparative studies of zebrafish, chick, Rana and an ancient frog species showed that chick and zebrafish prestin lacked NLC. Ancient frog's prestin was functionally different from Rana. CONCLUSIONS: We mapped and sequenced the SLC26A5 of the Rana catesbeiana from its inner ear cDNA using RNA-Seq. The Rana SLC26A5 cDNA was 2292 bp long, encoding a polypeptide of 763 amino acid residues, with 40% identity to mammals. This new coding gene could encode a functionally active protein conferring NLC to both frog HCs and the mammalian cell line. While comparing to its orthologs, the amphibian prestin has been evolutionarily changing its function and becomes more advanced than avian and teleost prestin.

Mathematical modeling of chemotaxis guided amoeboid cell swimming.

Cells and microorganisms adopt various strategies to migrate in response to different environmental stimuli. To date, many modeling research has focused on the crawling-basedDictyostelium discoideum(Dd) cells migration induced by chemotaxis, yet recent experimental results reveal that even without adhesion or contact to a substrate, Dd cells can still swim to follow chemoattractant signals. In this paper, we develop a modeling framework to investigate the chemotaxis induced amoeboid cell swimming dynamics. A minimal swimming system consists of one deformable Dd amoeboid cell and a dilute suspension of bacteria, and the bacteria produce chemoattractant signals that attract the Dd cell. We use themathematical amoeba modelto generate Dd cell deformation and solve the resulting low Reynolds number flows, and use a moving mesh based finite volume method to solve the reaction-diffusion-convection equation. Using the computational model, we show that chemotaxis guides a swimming Dd cell to follow and catch bacteria, while on the other hand, bacterial rheotaxis may help the bacteria to escape from the predator Dd cell.

Dose-Dependent Pattern of Cochlear Synaptic Degeneration in C57BL/6J Mice Induced by Repeated Noise Exposure.

It is widely accepted that even a single acute noise exposure at moderate intensity that induces temporary threshold shift (TTS) can result in permanent loss of ribbon synapses between inner hair cells and afferents. However, effects of repeated or chronic noise exposures on the cochlear synapses especially medial olivocochlear (MOC) efferent synapses remain elusive. Based on a weeklong repeated exposure model of bandwidth noise over 2-20 kHz for 2 hours at seven intensities (88 to 106 dB SPL with 3 dB increment per gradient) on C57BL/6J mice, we attempted to explore the dose-response mechanism of prolonged noise-induced audiological dysfunction and cochlear synaptic degeneration. In our results, mice repeatedly exposed to relatively low-intensity noise (88, 91, and 94 dB SPL) showed few changes on auditory brainstem response (ABR), ribbon synapses, or MOC efferent synapses. Notably, repeated moderate-intensity noise exposures (97 and 100 dB SPL) not only caused hearing threshold shifts and the inner hair cell ribbon synaptopathy but also impaired MOC efferent synapses, which might contribute to complex patterns of damages on cochlear function and morphology. However, repeated high-intensity (103 and 106 dB SPL) noise exposures induced PTSs mainly accompanied by damages on cochlear amplifier function of outer hair cells and the inner hair cell ribbon synaptopathy, rather than the MOC efferent synaptic degeneration. Moreover, we observed a frequency-dependent vulnerability of the repeated acoustic trauma-induced cochlear synaptic degeneration. This study provides a sight into the hypothesis that noise-induced cochlear synaptic degeneration involves both afferent (ribbon synapses) and efferent (MOC terminals) pathology. The pattern of dose-dependent pathological changes induced by repeated noise exposure at various intensities provides a possible explanation for the complicated cochlear synaptic degeneration in humans. The underlying mechanisms remain to be studied in the future.

An In Vitro Study on Prestin Analog Gene in the Bullfrog Hearing Organs.

The prestin-based active process in the mammalian outer hair cells (OHCs) is believed to play a crucial role in auditory signal amplification in the cochlea. Prestin belongs to an anion transporter family (SLC26A). It is densely expressed in the OHC lateral plasma membrane and functions as a voltage-dependent motor protein. Analog genes can be found in the genome of nonmammalian species, but their functions in hearing are poorly understood. In the present study, we used the gerbil prestin sequence as a template and identified an analog gene in the bullfrog genome. We expressed the gene in a stable cell line (HEK293T) and performed patch-clamp recording. We found that these cells exhibited prominent nonlinear capacitance (NLC), a widely accepted assay for prestin functioning as a motor protein. Upon close examination, the key parameters of this NLC are comparable to that conferred by the gerbil prestin, and nontransfected cells failed to display NLC. Lastly, we performed patch-clamp recording in HCs of all three hearing organs in bullfrog. HCs in both the sacculus and the amphibian papilla exhibited a capacitance profile that is similar to NLC while HCs in the basilar papilla showed no sign of NLC. Whether or not this NLC-like capacitance change is involved in auditory signal amplification certainly requires further examination; our results represent the first and necessary step in revealing possible roles of prestin in the active hearing processes found in many nonmammalian species.

Cell Sorting and Noise-Induced Cell Plasticity Coordinate to Sharpen Boundaries between Gene Expression Domains.

A fundamental question in biology is how sharp boundaries of gene expression form precisely in spite of biological variation/noise. Numerous mechanisms position gene expression domains across fields of cells (e.g. morphogens), but how these domains are refined remains unclear. In some cases, domain boundaries sharpen through differential adhesion-mediated cell sorting. However, boundaries can also sharpen through cellular plasticity, with cell fate changes driven by up- or down-regulation of gene expression. In this context, we have argued that noise in gene expression can help cells transition to the correct fate. Here we investigate the efficacy of cell sorting, gene expression plasticity, and their combination in boundary sharpening using multi-scale, stochastic models. We focus on the formation of hindbrain segments (rhombomeres) in the developing zebrafish as an example, but the mechanisms investigated apply broadly to many tissues. Our results indicate that neither sorting nor plasticity is sufficient on its own to sharpen transition regions between different rhombomeres. Rather the two have complementary strengths and weaknesses, which synergize when combined to sharpen gene expression boundaries.

Gene Expression Noise Enhances Robust Organization of the Early Mammalian Blastocyst.

A critical event in mammalian embryo development is construction of an inner cell mass surrounded by a trophoectoderm (a shell of cells that later form extraembryonic structures). We utilize multi-scale, stochastic modeling to investigate the design principles responsible for robust establishment of these structures. This investigation makes three predictions, each supported by our quantitative imaging. First, stochasticity in the expression of critical genes promotes cell plasticity and has a critical role in accurately organizing the developing mouse blastocyst. Second, asymmetry in the levels of noise variation (expression fluctuation) of Cdx2 and Oct4 provides a means to gain the benefits of noise-mediated plasticity while ameliorating the potentially detrimental effects of stochasticity. Finally, by controlling the timing and pace of cell fate specification, the embryo temporally modulates plasticity and creates a time window during which each cell can continually read its environment and adjusts its fate. These results suggest noise has a crucial role in maintaining cellular plasticity and organizing the blastocyst.

Analysis of a model microswimmer with applications to blebbing cells and mini-robots.

Recent research has shown that motile cells can adapt their mode of propulsion depending on the environment in which they find themselves. One mode is swimming by blebbing or other shape changes, and in this paper we analyze a class of models for movement of cells by blebbing and of nano-robots in a viscous fluid at low Reynolds number. At the level of individuals, the shape changes comprise volume exchanges between connected spheres that can control their separation, which are simple enough that significant analytical results can be obtained. Our goal is to understand how the efficiency of movement depends on the amplitude and period of the volume exchanges when the spheres approach closely during a cycle. Previous analyses were predicated on wide separation, and we show that the speed increases significantly as the separation decreases due to the strong hydrodynamic interactions between spheres in close proximity. The scallop theorem asserts that at least two degrees of freedom are needed to produce net motion in a cyclic sequence of shape changes, and we show that these degrees can reside in different swimmers whose collective motion is studied. We also show that different combinations of mode sharing can lead to significant differences in the translation and performance of pairs of swimmers.