Symmetric Division Research Articles

Dexpanthenol improved stem cells against cisplatin-induced kidney injury by inhibition of TNF-α, TGFβ-1, β-catenin, and fibronectin pathways

IntroductionCisplatin interacts with DNA and induces an immunological response and reactive oxygen species, which are nephrotoxic mediators. Stem cells self-renew through symmetric divisions and can develop into other cell types due to their multipotency. Dexpanthenol has been proven to protect against renalinjury. AimThis study aims to demonstrate that dexpanthenol could improve the effect of adipose-derived mesenchymal stem cells (ADMSC) against cisplatin-induced acute kidney injury. MethodsSixty male Sprague-Dawley rats were divided into 5 groups (N = 12): control, cisplatin, cisplatin & dexpanthenol, cisplatin & ADMSC, and cisplatin & dexpanthenol & ADMSCs. On the 5th day following cisplatin injection, half the rats in each group were sacrificed, and the other half were sacrificed on the 12th day. Histopathological examination, molecular studies (IL-6, Bcl2, TGFβ-1, Caspase-3, Fibronectin, and β-catenin), antioxidants (superoxide dismutase and catalase), and renal function were all investigated. ResultsIn contrast to cisplatin group, the dexpanthenol and ADMSCs treatments significantly decreased renal function and oxidative stress while significantly enhancing antioxidants. Dexpanthenol improved stem cells by significantly down-regulating caspase-3, IL-6, TGF-β1, Fibronectin, and β-catenin and significantly up-regulating Bcl2 and CD34, which reversed the cisplatin effect. ConclusionDexpanthenol enhanced ADMSCs' ability to protect against cisplatin-induced AKI by decreasing inflammation, apoptosis, and fibrosis.

A Study on the Energy of Graphs and Its Applications

In this paper, we dealt with two very well-known eigenvalue-based molecular descriptors such as the energy of graph ( E ( G ) ) and Estrada index ( E E ( G ) ) . We test their predictive potential of some physicochemical properties of polycyclic aromatic hydrocarbons using a data set of benzenoid hydrocarbons. We stabilized a relation of these two indices with some well-known degree-based topological indices such as the first Zagreb index, second Zagreb index, F-index, Randić index, Reciprocal Randić index, Atom bond connectivity index, sum-connectivity index, Geometric-arithmetic, Harmonic index, symmetric division deg index, and redefined Zagreb index.

Impact of hybrid surfaces on the droplet breakup dynamics in microgravity slug flow: A dynamic contact angle analysis

Microfluidic devices, which enable precise control and manipulation of fluids at the microscale, have revolutionized various fields, including chemical synthesis and space technology. A comprehensive understanding of fluid behavior under diverse conditions, particularly in microgravity, is essential for optimizing the design and performance of these devices. This paper aims to investigate the effects of discontinuous wettability on droplet breakup structures under microgravity conditions using a microchannel wall. The approach we adopt is underpinned by the volume-of-fluid methodology, an efficient technique renowned for its accurate resolution of the fluid interface in a two-phase flow. Furthermore, a modified dynamic contact angle model is employed to precisely predict the shape of the droplet interface at and near the wall. Our comprehensive model considers influential parameters such as slug length and droplet generation frequency, thereby providing crucial insights into their impact on the two-phase interface velocity. Validated against existing literature data, our model explores the impact of various configurations of discontinuous wettability on breakup morphology. Our findings highlight the significance of employing a dynamic contact angle methodology for making accurate predictions of droplet shape, which is influenced by the wall contact angle. Emphasis is placed particularly on the effects of slug length and droplet generation frequency. Notably, we demonstrate that the use of a hybrid surface at the junction section allows for precise control over the shape and size of the daughter droplets, contrasting with the symmetrical division observed on uniformly hydrophilic or superhydrophobic surfaces. This study contributes valuable insights into the complex dynamics of the droplet breakup process, which has profound implications for the design and optimization of microfluidic devices operating under microgravity conditions. Such insights are further poised to augment applications in space exploration, microreactors, and more.

The impact of TP53 activation and apoptosis in primary hereditary microcephaly.

Autosomal recessive primary microcephaly (MCPH) is a constellation of disorders that share significant brain size reduction and mild to moderate intellectual disability, which may be accompanied by a large variety of more invalidating clinical signs. Extensive neural progenitor cells (NPC) proliferation and differentiation are essential to determine brain final size. Accordingly, the 30 MCPH loci mapped so far (MCPH1-MCPH30) encode for proteins involved in microtubule and spindle organization, centriole biogenesis, nuclear envelope, DNA replication and repair, underscoring that a wide variety of cellular processes is required for sustaining NPC expansion during development. Current models propose that altered balance between symmetric and asymmetric division, as well as premature differentiation, are the main mechanisms leading to MCPH. Although studies of cellular alterations in microcephaly models have constantly shown the co-existence of high DNA damage and apoptosis levels, these mechanisms are less considered as primary factors. In this review we highlight how the molecular and cellular events produced by mutation of the majority of MCPH genes may converge on apoptotic death of NPCs and neurons, via TP53 activation. We propose that these mechanisms should be more carefully considered in the alterations of the sophisticated equilibrium between proliferation, differentiation and death produced by MCPH gene mutations. In consideration of the potential druggability of cell apoptotic pathways, a better understanding of their role in MCPH may significantly facilitate the development of translational approaches.

Polarized SCAR and the Arp2/3 complex regulate apical cortical remodeling in asymmetrically dividing neuroblasts

Although the formin-nucleated actomyosin cortex has been shown to drive the changes in cell shape that accompany animal cell division in both symmetric and asymmetric cell divisions, the mitotic role of cortical Arp2/3-nucleated actin networks remain unclear. Here using asymmetrically dividing Drosophila neural stem cells as a model system, we identify a pool of membrane protrusions that form at the apical cortex of neuroblasts as they enter mitosis. Strikingly, these apically localized protrusions are enriched in SCAR, and depend on SCAR and Arp2/3 complexes for their formation. Because compromising SCAR or the Arp2/3 complex delays the apical clearance of Myosin II at the onset of anaphase and induces cortical instability at cytokinesis, these data point to a role for an apical branched actin filament network in fine-tuning the actomyosin cortex toenable the precise control of cell shape changes during an asymmetric cell division.

Establishing massively parallel models to examine the influence of cell heterogeneity on tumor growth

Parallel 3D cellular automaton models of tumor growth can efficiently capture emergent morphology. We extended a 2D growth model to 3D to examine the influence of symmetric division in heterogeneous tumors on growth dynamics. As extending to 3D severely increased time-to-solution, we parallelized the model using N-body, lattice halo exchange, and adaptive communication schemes. Supplementing prior work from Tanade et al. (2022), we demonstrated over 55x speedup and evaluated performance on ≤30 nodes of Stampede2. This work established a framework to parametrically study 3D growth dynamics, and of the cancer phenotypes we studied, the parallel model better scaled when tumor boundaries were radially symmetric.

Studying histone inheritance in different systems using imaging-based methods and perspectives.

Understanding cell identity is critically important in the fields of cell and developmental biology. During cell division, a mother cell duplicates the genetic material and cellular components to give rise to two daughter cells. While both cells receive the same genetic information, they can take on similar or different cell fates, resulting from a symmetric or asymmetric division. These fates can be modulated by epigenetic mechanisms that can alter gene expression without changing genetic information. Histone proteins, which wrap DNA into fundamental units of chromatin, are major carriers of epigenetic information and can directly influence gene expression and other cellular functions through their interactions with DNA. While it has been well studied how the genetic information is duplicated and segregated, how epigenetic information, such as histones, are inherited through cell division is still an area of investigation. Since canonical histone proteins are incorporated into chromatin during DNA replication and can be modified over time, it is important to study their inheritance within the context of the cell cycle. Here, we outline the biological basis of histone inheritance as well as the imaging-based experimental design that can be used to study this process. Furthermore, we discuss various studies that have investigated this phenomenon with the focus on asymmetrically dividing cells in different systems. This synopsis provides insight into histone inheritance within the context of the cell cycle, along with the technical methods and considerations that must be taken when studying this process in vivo.

Symmetric Division Degree Invariants of Join Total and Mid Graphs

Symmetric Division Degree Invariants of Join Total and Mid Graphs

An R2R3 MYB transcription factor PsFLP regulates the symmetric division of guard mother cells during stomatal development in Pisum sativum.

MYB transcriptional regulators belong to one of the most significant transcription factors families in plants, among which R2R3-MYB transcription factors are involved in plant growth and development, hormone signal transduction, and stress response. Two R2R3-MYB transcription factors, FLP and its paralogous AtMYB88, redundantly regulate the symmetrical division of guard mother cells (GMCs), and abiotic stress response in Arabidopsis thaliana. Only one orthologue gene of FLP was identified in pea (Pisum sativum FLP; PsFLP). In this study, we explored the gene function of PsFLP by virus-induced gene silencing (VIGS) technology. The phenotypic analysis displayed that the silencing of PsFLP expression led to the abnormal development of stomata and the emergence of multiple guard cells tightly united. In addition, the abnormal stomata of flp could be fully rescued by PsFLP driven by the FLP promoter. In conclusion, the results showed that PsFLP plays a conservative negative role in regulating the symmetric division of GMC during stomatal development. Based on real-time quantitative PCR, the relative expressions of AAO3, NCED3, and SnRK2.3 significantly increased in the flp pFLP::PsFLP plants compared to mutant, indicating that PsFLP might be involved in drought stress response. Thus, PsFLP regulates the genes related to cell cycle division during the stomatal development of peas and participates in response to drought stress. The study provides a basis for further research on its function and application in leguminous crop breeding.

Linking asymmetric cell division, CD8+ T cell fate, and signal strength

Through live imaging of CD8+ Tcells carrying a fate reporter, Gräbnitz etal. directly linked (a)symmetric division to Tcell fate.1 Asymmetry during the first division ensured the generation of stem-like CD8+ Tcells following strong Tcell stimulation.

Performance Analysis of Orthogonal Multiplexing Techniques for PLC Systems with Low Cyclic Prefix Length and Symbol Timing Offset.

This paper investigates the degradation caused by interference resulting from cyclic prefix violation and symbol timing offset in narrowband power line communication systems. In this sense, it presents a unified formulation from which Hermitian symmetric orthogonal frequency division multiplexing (HS-OFDM), orthogonal chirp division multiplexing (OCDM), single-carrier cyclic prefix (SCCP), and orthogonal time-frequency division multiplexing (OTFDM) can be easily derived. The paper then provides closed-form expressions for quantifying the aforementioned interference in the presence of a frequency domain equalizer. The numerical analyses exhibit the performances of these schemes under various data communication conditions, such as the availability of channel state information, the presence or absence of interference, modeling of additive noise as a white or colored Gaussian random process, frequency domain equalizer type, and the use of bit and power allocation techniques. The closed-form expressions and performance analyses regarding achievable data rate and bit error probability provide guidance for dealing with distinct constraints in narrowband power line communication (PLC) systems using the HS-OFDM, OCDM, SCCP, or OTFDM scheme. Lastly, the unified formulation and results obtained motivate the design of multi-scheme transceivers.

Microtubule competition and cell growth recenter the nucleus after anaphase in fission yeast.

Cells actively position their nuclei based on their activity. In fission yeast, microtubule-dependent nuclear centering is critical for symmetrical cell division. After spindle disassembly at the end of anaphase, the nucleus recenters over an ∼90-min period, approximately half of the duration of the cell cycle. Live-cell and simulation experiments support the cooperation of two distinct microtubule competition mechanisms in the slow recentering of the nucleus. First, a push-push mechanism acts from spindle disassembly to septation and involves the opposing actions of the mitotic spindle pole body microtubules that push the nucleus away from the ends of the cell, while a postanaphase array of microtubules baskets the nucleus and limits its migration toward the division plane. Second, a slow-and-grow mechanism slowly centers the nucleus in the newborn cell by a combination of microtubule competition and asymmetric cell growth. Our work underlines how intrinsic properties of microtubules differently impact nuclear positioning according to microtubule network organization and cell size.

Stability of asymmetric cell division: A deformable cell model of cytokinesis applied to C. elegans

Cell division during early embryogenesis is linked to key morphogenic events such as embryo symmetry breaking and tissue patterning. It is thought that the physical surrounding of cells together with cell intrinsic cues act as a mechanical “mold,” guiding cell division to ensure these events are robust. To quantify how cell division is affected by the mechanical and geometrical environment, we present a novel computational mechanical model of cytokinesis, the final phase of cell division. Simulations with the model reproduced experimentally observed furrow dynamics and describe the volume ratio of daughter cells in asymmetric cell divisions, based on the position and orientation of the mitotic spindle. For dividing cells in geometrically confined environments, we show how the orientation of confinement relative to the division axis modulates the volume ratio in asymmetric cell division. Further, we quantified how cortex viscosity and surface tension determine the shape of a dividing cell and govern bubble-instabilities in asymmetric cell division. Finally, we simulated the formation of the three body axes via sequential (a)symmetric divisions up until the six-cell stage of early C. elegans development, which proceeds within the confines of an eggshell. We demonstrate how model input parameters spindle position and orientation provide sufficient information to reliably predict the volume ratio of daughter cells during the cleavage phase of development. However, for egg geometries perturbed by compression, the model predicts that a change in confinement alone is insufficient to explain experimentally observed differences in cell volume. This points to an effect of the compression on the spindle positioning mechanism. Additionally, the model predicts that confinement stabilizes asymmetric cell divisions against bubble-instabilities.

Reliable and robust control of nucleus centering is contingent on nonequilibrium force patterns

Cell centers their division apparatus to ensure symmetric cell division, a challenging task when the governing dynamics is stochastic. Using fission yeast, we show that the patterning of nonequilibrium polymerization forces of microtubule (MT) bundles controls the precise localization of spindle pole body (SPB), and hence the division septum, at the onset of mitosis. We define two cellular objectives, reliability, the mean SPB position relative to the geometric center, and robustness, the variance of the SPB position, which are sensitive to genetic perturbations that change cell length, MT bundle number/orientation, and MT dynamics. We show that simultaneous control of reliability and robustness is required to minimize septum positioning error achieved by the wild type (WT). A stochastic model for the MT-based nucleus centering, with parameters measured directly or estimated using Bayesian inference, recapitulates the maximum fidelity of WT. Using this, we perform a sensitivity analysis of the parameters that control nuclear centering.

Abstract 1338: Subpopulations of cancer associated fibroblasts serve as cancer stem cell niche in ovarian cancer via activation of non-canonical Wnt signaling

Abstract Ovarian cancer (OC) is the most lethal gynecologic cancer and the 5th leading cause of cancer-related deaths among women in the US. One of the main reasons for the poor outcome is a high recurrence rate and development of chemoresistance. The standard care involves debulking surgery and carbo-taxol chemotherapy. While most patients respond well initially, a small fraction of OC cells survive - these persister cells are enriched in cancer stem cells (CSCs), and are capable of tumor initiation and cause relapse. Most studies on OC stem cells (OCSCs) have focused on their cell-intrinsic properties and not much is known about the role of the tumor microenvironment (TME) in regulating their growth, fate, and sustenance. Cancer-associated fibroblasts (CAFs) are a key constituent of the OC TME and have been reported to play important roles in regulating tumorigenesis, metastasis, and immune evasion. Moreover, the residual tumors following neo-adjuvant chemotherapy are highly fibrotic. Our studies using matched pre- and post-chemotherapy OC patient tumors revealed an enrichment in OCSCs and CAFs following chemotherapy. Using heterotypic 3D cocultures of patient-derived CAFs and OC cells and in vivo limiting dilution assay, we found that CAFs could induce OCSCs. CAFs stimulated symmetric division of OCSCs as well as dedifferentiation of some non-OCSCs. Using a novel interface interaction assay that we developed, we found that CAFs could influence only those OC cells that are in their immediate neighborhood. We have identified the underlying mechanism involving a non-canonical Wnt signaling pathway in the OCSCs induced by Wnt5a secreted by CAFs. Using functional rescue experiments, we determined that Wnt5a acted via its coreceptor ROR2 on the OCSCs that activated PKC and CREB1 to induce stemness. Inhibiting the CAF-OCSC crosstalk using a Wnt5a-specific inhibitor, Box5 abrogated the effects of CAFs on OCSCs both in vitro and in vivo. While Box5 treatment alone was sufficient to inhibit tumor growth in vivo, its combination with carboplatin sensitized tumors to carboplatin by eradicating residual OCSCs. CAFs are heterogenous and not all CAFs are capable of inducing OCSCs, similarly, only a subpopulation of OC cells can respond to CAFs and dedifferentiate into OCSCs. We performed single-cell RNA-seq using heterotypic 3D cocultures of patient-derived CAFs and OC cells, and characterized the pathways activated in Wnt5ahigh CAFs. Using trajectory analysis, we identified OC subpopulations that respond to CAF signals and become OCSCs. In summary, we have identified a novel mechanism by which a subpopulation of CAFs in the OC TME act as OCSC niche. Our research provides compelling evidence in support of targeting Wnt5a, in combination with the standard of care carbo-taxol chemotherapy, to prevent OC relapse and chemoresistance. Citation Format: Xue Xiao, Yiming Fang, David Pepin, Dmitriy Zamarin, Anirban K. Mitra. Subpopulations of cancer associated fibroblasts serve as cancer stem cell niche in ovarian cancer via activation of non-canonical Wnt signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1338.

XLF/Cernunnos loss impairs mouse brain development by altering symmetric proliferative divisions of neural progenitors

XLF/Cernunnos is a component of the ligation complex used in classical non-homologous end-joining (cNHEJ), a major DNA double-strand break (DSB) repair pathway. We report neurodevelopmental delays and significant behavioral alterations associated with microcephaly in Xlf-/- mice. This phenotype, reminiscent of clinical and neuropathologic features in humans deficient in cNHEJ, is associated with a low level of apoptosis of neural cells and premature neurogenesis, which consists of an early shift of neural progenitors from proliferative to neurogenic divisions during brain development. We show that premature neurogenesis is related to an increase in chromatid breaks affecting mitotic spindle orientation, highlighting a direct link between asymmetric chromosome segregation and asymmetric neurogenic divisions. This study reveals thus that XLF is required for maintaining symmetric proliferative divisions of neural progenitors during brain development and shows that premature neurogenesis may play a major role in neurodevelopmental pathologies caused by NHEJ deficiency and/or genotoxic stress.

Symmetric Division Deg Index: Extremal Results and Bounds

Existing studies show that the symmetric division deg (SDD) index deserves to be treated as a useful and practicable molecular descriptor, preferable to some of the more widely used ones. The primary purpose of this review is to summarize the existing extremal results and bounds for the SDD index. Several open problems regarding the aforementioned index, arising from the known results, are also proposed.

Kinetics of blood cell differentiation during hematopoiesis revealed by quantitative long-term live imaging.

Stem cells typically reside in a specialized physical and biochemical environment that facilitates regulation of their behavior. For this reason, stem cells are ideally studied in contexts that maintain this precisely constructed microenvironment while still allowing for live imaging. Here, we describe a long-term organ culture and imaging strategy for hematopoiesis in flies that takes advantage of powerful genetic and transgenic tools available in this system. We find that fly blood progenitors undergo symmetric cell divisions and that their division is both linked to cell size and is spatially oriented. Using quantitative imaging to simultaneously track markers for stemness and differentiation in progenitors, we identify two types of differentiation that exhibit distinct kinetics. Moreover, we find that infection-induced activation of hematopoiesis occurs through modulation of the kinetics of cell differentiation. Overall, our results show that even subtle shifts in proliferation and differentiation kinetics can have large and aggregate effects to transform blood progenitors from a quiescent to an activated state.

Coevolution of reproducers and replicators at the origin of life and the conditions for the origin of genomes

There are two fundamentally distinct but inextricably linked types of biological evolutionary units, reproducers and replicators. Reproducers are cells and organelles that reproduce via various forms of division and maintain the physical continuity of compartments and their content. Replicators are genetic elements (GE), including genomes of cellular organisms and various autonomous elements, that both cooperate with reproducers and rely on the latter for replication. All known cells and organisms comprise a union between replicators and reproducers. We explore a model in which cells emerged via symbiosis between primordial "metabolic" reproducers (protocells) which evolved, on short time scales, via a primitive form of selection and random drift, and mutualist replicators. Mathematical modeling identifies the conditions, under which GE-carrying protocells can outcompete GE-less ones, taking into account that, from the earliest stages of evolution, replicators split into mutualists and parasites. Analysis of the model shows that, for the GE-containing protocells to win the competition and to be fixed in evolution, it is essential that the birth-death process of the GE is coordinated with the rate of protocell division. At the early stages of evolution, random, high-variance cell division is advantageous compared with symmetrical division because the former provides for the emergence of protocells containing only mutualists, preventing takeover by parasites. These findings illuminate the likely order of key events on the evolutionary route from protocells to cells that involved the origin of genomes, symmetrical cell division, and antiparasite defense systems.

Loss of the Maternal Effect Gene Nlrp2 Alters the Transcriptome of Ovulated Mouse Oocytes and Impacts Expression of Histone Demethylase KDM1B.

The subcortical maternal complex (SCMC) is a multiprotein complex in oocytes and preimplantation embryos that is encoded by maternal effect genes. The SCMC is essential for zygote-to-embryo transition, early embryogenesis, and critical zygotic cellular processes, including spindle positioning and symmetric division. Maternal deletion of Nlrp2, which encodes an SCMC protein, results in increased early embryonic loss and abnormal DNA methylation in embryos. We performed RNA sequencing on pools of meiosis II (MII) oocytes from wild-type and Nlrp2-null female mice that were isolated from cumulus-oocyte complexes (COCs) after ovarian stimulation. Using a mouse reference genome-based analysis, we found 231 differentially expressed genes (DEGs) in Nlrp2-null compared to WT oocytes (123 up- and 108 downregulated; adjusted p < 0.05). The upregulated genes include Kdm1b, a H3K4 histone demethylase required during oocyte development for the establishment of DNA methylation marks at CpG islands, including those at imprinted genes. The identified DEGs are enriched for processes involved in neurogenesis, gland morphogenesis, and protein metabolism and for post-translationally methylated proteins. When we compared our RNA sequencing data to an oocyte-specific reference transcriptome that contains many previously unannotated transcripts, we found 228 DEGs, including genes not identified with the first analysis. Interestingly, 68% and 56% of DEGs from the first and second analyses, respectively, overlap with oocyte-specific hyper- and hypomethylated domains. This study shows that there are substantial changes in the transcriptome of mouse MII oocytes from female mice with loss of function of Nlrp2, a maternal effect gene that encodes a member of the SCMC.