Division Events Research Articles

NO-Stressed Y. pseudotuberculosis Has Decreased Cell Division Rates in the Mouse Spleen.

Fluorescence dilution approaches can detect bacterial cell division events and can detect if there are differential rates of cell division across individual cells within a population. This approach typically involves inducing expression of a fluorescent protein and then tracking partitioning of fluorescence into daughter cells. However, fluorescence can be diluted very quickly within a rapidly replicating population, such as pathogenic bacterial populations replicating within host tissues. To overcome this limitation, we have generated two revTetR reporter constructs, where either mCherry or yellow fluorescent protein (YFP) is constitutively expressed and repressed by addition of tetracyclines, resulting in fluorescence dilution within defined time frames. We show that fluorescent signals are diluted in replicating populations and that signal accumulates in growth-inhibited populations, including during nitric oxide (NO) exposure. Furthermore, we show that tetracyclines can be delivered to the mouse spleen during Yersinia pseudotuberculosis infection and defined a drug concentration that results in even exposure of cells to tetracyclines. We then used this system to visualize bacterial cell division within defined time frames postinfection. revTetR-mCherry allowed us to detect slow-growing cells in response to NO in culture; however, this strain had a growth defect within mouse tissues, which complicated results. To address this issue, we constructed revTetR-YFP using the less toxic YFP and showed that heightened NO exposure correlated with heightened YFP signal, indicating decreased cell division rates within this subpopulation in vivo. This revTetR reporter will provide a critical tool for future studies to identify and isolate slowly replicating bacterial subpopulations from host tissues.

P-277 An artificial intelligence (AI) deselection model for top-quality blastocysts: algorithmic analysis of morphokinetic features for aneuploidy may increase implantation rates

Abstract Study question Can an AI deselection model identify distinct morphokinetic patterns in top-quality blastocyst with unknown ploidy that fail to implant? Summary answer An AI based deselection model was able to predict implantation failure based on morphokinetic features previously found to associate with aneuploidy. What is known already Aneuploidy is the most common explanation for implantation failure of high-quality blastocysts. Yet, high-quality blastocysts with unknown ploidy that fail to implant are often morphologically indistinguishable from blastocysts that succeed to implant. Our previously published results (ESHRE 2021) demonstrated that aneuploid blastocysts were more likely to reach development events (t2-t8) later, and that the timing between each event was statistically longer (p < 0.001), when compared to euploid embryos. Given that delayed morphokinetic rates are tightly linked to ploidy, we investigated whether similar known morphokinetic features were associated with implantation failure in top-graded embryos. Study design, size, duration Time-lapse sequences of 3,259 top-quality blastocysts from fresh single embryo transfer cycles with known implantation outcomes were analyzed using an AI-based algorithm. The algorithm utilized convolutional neural network extracted temporal features based on multiple morphokinetic parameters known to associate with ploidy. Participants/materials, setting, methods time-lapse sequences and morphokinetic events were algorithmically analyzed to measure the rate of mitotic division events and compare the number of embryos in each category (implanted/nonimplanted) that reached each developmental event at least one standard deviation (SD) later than the mean for implanted embryos. Main results and the role of chance Results showed statistical differences in the following morphokinetic features between the two categories: t2, t3, t4, and t3-t4 (p < 0.05). Implanted top-graded blastocysts were likely to reach t2, t3, and t4 after 25.23 ± 3.8 SD, 36.06 ± 3.4 SD, and 37.14 hours ±3.6 SD, respectively. The time gap between t3 and t4 was found to be 12.25 hours ± 5.31 SD. Given this, we followed the methodology described above to propose cutoff values (in hours) that differentiated between non-implanted and implanted top-graded blastocysts based on their morphokinetic profiles. Implantation failure was found to be associated with the likelihood of reaching t2 after 28.61 hours (OR = 2.36, CI 0.96-5.77), t3 after 39.46 (OR = 3.48, CI 1.62-7.47), and t4 after 40.79 hours (OR = 2.23, CI 1.09- 4.53). A time gap between t3 and t4 of more than 17.56 hours was also associated with implantation failure (OR = 2.48, CI 1.12-5.48), indicating perturbed mitotic activity. The cutoff values proposed here were incorporated into the algorithm for optimized deselection of morphologically similar top-quality blastocysts with delayed morphokinetic profiles. Limitations, reasons for caution This study needs to be validated on a larger, multi-centric dataset that takes into account more morphokinetic features associated with ploidy in order to increase the robustness of our algorithm. Wider implications of the findings For the first time, our algorithmic model proposed here demonstrates the utility of an AI tool to deselect top-graded blastocysts that would otherwise be selected for transfer based on conventional morphologic assessment alone. Trial registration number Not Applicable

Timelapse viability assay to detect division and death of primary multiple myeloma cells in response to drug treatments with single cell resolution.

Heterogeneity among cancer cells and in the tumor microenvironment (TME) is thought to be a significant contributor to the heterogeneity of clinical therapy response observed between patients and can evolve over time. A primary example of this is multiple myeloma (MM), a generally incurable cancer where such heterogeneity contributes to the persistent evolution of drug resistance. However, there is a paucity of functional assays for studying this heterogeneity in patient samples or for assessing the influence of the patient TME on therapy response. Indeed, the population-averaged data provided by traditional drug response assays and the large number of cells required for screening remain significant hurdles to advancement. To address these hurdles, we developed a suite of accessible technologies for quantifying functional drug response to a panel of therapies in ex vivo three-dimensional culture using small quantities of a patient's own cancer and TME components. This suite includes tools for label-free single-cell identification and quantification of both cell division and death events with a standard brightfield microscope, an open-source software package for objective image analysis and feasible data management of multi-day timelapse experiments, and a new approach to fluorescent detection of cell death that is compatible with long-term imaging of primary cells. These new tools and capabilities are used to enable sensitive, objective, functional characterization of primary MM cell therapy response in the presence of TME components, laying the foundation for future studies and efforts to enable predictive assessment drug efficacy for individual patients.

Visualization of the Crossroads between a Nascent Infection Thread and the First Cell Division Event in Phaseolus vulgaris Nodulation

The development of a symbiotic nitrogen-fixing nodule in legumes involves infection and organogenesis. Infection begins when rhizobia enter a root hair through an inward structure, the infection thread (IT), which guides the bacteria towards the cortical tissue. Concurrently, organogenesis takes place by inducing cortical cell division (CCD) at the infection site. Genetic analysis showed that both events are well-coordinated; however, the dynamics connecting them remain to be elucidated. To visualize the crossroads between IT and CCD, we benefited from the fact that, in Phaseolus vulgaris nodulation, where the first division occurs in subepidermal cortical cells located underneath the infection site, we traced a Rhizobium etli strain expressing DsRed, the plant cytokinesis marker YFP-PvKNOLLE, a nuclear stain and cell wall auto-fluorescence. We found that the IT exits the root hair to penetrate an underlying subepidermal cortical (S-E) cell when it is concluding cytokinesis.

TedSim: temporal dynamics simulation of single-cell RNA sequencing data and cell division history.

Recently, lineage tracing technology using CRISPR/Cas9 genome editing has enabled simultaneous readouts of gene expressions and lineage barcodes, which allows for the reconstruction of the cell division tree and makes it possible to reconstruct ancestral cell types and trace the origin of each cell type. Meanwhile, trajectory inference methods are widely used to infer cell trajectories and pseudotime in a dynamic process using gene expression data of present-day cells. Here, we present TedSim (single-cell temporal dynamics simulator), which simulates the cell division events from the root cell to present-day cells, simultaneously generating two data modalities for each single cell: the lineage barcode and gene expression data. TedSim is a framework that connects the two problems: lineage tracing and trajectory inference. Using TedSim, we conducted analysis to show that (i) TedSim generates realistic gene expression and barcode data, as well as realistic relationships between these two data modalities; (ii) trajectory inference methods can recover the underlying cell state transition mechanism with balanced cell type compositions; and (iii) integrating gene expression and barcode data can provide more insights into the temporal dynamics in cell differentiation compared to using only one type of data, but better integration methods need to be developed.

ASPP2 maintains the integrity of mechanically stressed pseudostratified epithelia during morphogenesis

During development, pseudostratified epithelia undergo large scale morphogenetic events associated with increased mechanical stress. Using a variety of genetic and imaging approaches, we uncover that in the mouse E6.5 epiblast, where apical tension is highest, ASPP2 safeguards tissue integrity. It achieves this by preventing the most apical daughter cells from delaminating apically following division events. In this context, ASPP2 maintains the integrity and organisation of the filamentous actin cytoskeleton at apical junctions. ASPP2 is also essential during gastrulation in the primitive streak, in somites and in the head fold region, suggesting that it is required across a wide range of pseudostratified epithelia during morphogenetic events that are accompanied by intense tissue remodelling. Finally, our study also suggests that the interaction between ASPP2 and PP1 is essential to the tumour suppressor function of ASPP2, which may be particularly relevant in the context of tissues that are subject to increased mechanical stress.

Assessing the effect of spatial-temporal droughts on dominant crop yield changes in Central Malawi.

Central Malawi has intensely been subjected to different climate-related shocks such as floods, dry spells, and droughts, resulting in decreases in crop yields. Due to their recurrence arising from the effects of climate change, drought characterization, monitoring, and prediction are crucial in guiding agriculture-water users and planners to prepare drought risk management plans and early warning systems. This research analyzed droughts, using multiple drought indices and their impacts on dominant crops over Central Malawi. Forty years of hydro-meteorological data (1977-2017) from nine rain-gauging stations and crop yield data from 1983 to 2017 from four districts were analyzed. The study discovered that drought events in the Agricultural Development Division (ADD) are highly a function of rainfall deficit and high temperatures. The results highlighted that the rainfall patterns in the area are not dependable, calling for the utilization of climate-smart irrigation systems such as drip irrigation and rainwater harvesting technologies. Furthermore, we achieved that crops such as cassava and groundnuts must be promoted to withstand the long water stress duration. These crops also have a multiplier effect; hence, they can enhance food security in the region. This study recommends that using more robust variables in drought analysis studies is necessary for effective drought monitoring and early warning systems. In corroboration with disaster management NGOs, it is recommended that the government should be proactive in developing integrated drought management policies and planning strategies for drought adaptation and mitigation.

Differences in cell death and division rules can alter tissue rigidity and fluidization.

Tissue mechanical properties such as rigidity and fluidity, and changes in these properties driven by jamming-unjamming transitions (UJT), have come under recent highlight as mechanical markers of health and disease in various biological processes including cancer. However, most analyses of these mechanical properties and UJT have sidestepped the effect of cellular death and division in these systems. Cellular apoptosis (programmed cell death) and mitosis (cell division) can drive significant changes in tissue properties. The balance between the two is crucial in maintaining tissue function, and an imbalance between the two is seen in situations such as cancer progression, wound healing and necrosis. In this work we investigate the impact of cell death and division on tissue mechanical properties, by incorporating specific mechanosensitive triggers of cell death and division based on the size and geometry of the cell within in silico models of tissue dynamics. Specifically, we look at cell migration, tissue response to external stress, tissue extrusion propensity and self-organization of different cell types within the tissue, as a function of cell death and division and the rules that trigger these events. We find that not only do cell death and division events significantly alter tissue mechanics when compared to systems without these events, but that the choice of triggers driving these cell death and division events also alters the predicted tissue mechanics and overall system behavior.

A simple method for the application of exogenous phytohormones to the grass leaf base protodermal zone to improve grass leaf epidermis development research

BackgroundThe leaf epidermis functions to prevent the loss of water and reduce gas exchange. As an interface between the plant and its external environment, it helps prevent damage, making it an attractive system for studying cell fate and development. In monocotyledons, the leaf epidermis grows from the basal meristem that contains protodermal cells. Leaf protoderm zone is covered by the leaf sheath or coleoptile in maize and wheat, preventing traditional exogenous phytohormone application methods, such as directly spraying on the leaf surface or indirectly via culture media, from reaching the protoderm areas directly. The lack of a suitable application method limits research on the effect of phytohormone on the development of grass epidermis.ResultsHere, we describe a direct and straightforward method to apply exogenous phytohormones to the leaf protoderms of maize and wheat. We used the auxin analogs 2,4-D and cytokinin analogs 6-BA to test the system. After 2,4-D treatment, the asymmetrical division events and initial stomata development were decreased, and the subsidiary cells were induced in maize, the number of GMC (guard mother cell), SMC (subsidiary mother cell) and young stomata were increased in wheat, and the size of the epidermal cells increased after 6-BA treatment in maize. Thus, the method is suitable for the application of phytohormone to the grass leaf protodermal areas.ConclusionsThe method to apply hormones to the mesocotyls of maize and wheat seedlings is simple and direct. Only a small amount of externally applied substances are needed to complete the procedure in this method. The entire experimental process lasts for ten days generally, and it is easy to evaluate the phytohormones’ effect on the epidermis development.

Visualization of individual cell division history in complex tissues using iCOUNT.

SummaryThe division potential of individual stem cells and the molecular consequences of successive rounds of proliferation remain largely unknown. Here, we developed an inducible cell division counter (iCOUNT) that reports cell division events in human and mouse tissues in vitro and in vivo. Analyzing cell division histories of neural stem/progenitor cells (NSPCs) in the developing and adult brain, we show that iCOUNT can provide novel insights into stem cell behavior. Further, we use single-cell RNA sequencing (scRNA-seq) of iCOUNT-labeled NSPCs and their progenies from the developing mouse cortex and forebrain-regionalized human organoids to identify functionally relevant molecular pathways that are commonly regulated between mouse and human cells, depending on individual cell division histories. Thus, we developed a tool to characterize the molecular consequences of repeated cell divisions of stem cells that allows an analysis of the cellular principles underlying tissue formation, homeostasis, and repair.

Continuous rate modeling of bacterial stochastic size dynamics.

Bacterial division is an inherently stochastic process with effects on fluctuations of protein concentration and phenotype variability. Current modeling tools for the stochastic short-term cell-size dynamics are scarce and mainly phenomenological. Here we present a general theoretical approach based on the Chapman-Kolmogorov equation incorporating continuous growth and division events as jump processes. This approach allows us to include different division strategies, noisy growth, and noisy cell splitting. Considering bacteria synchronized from their last division, we predict oscillations in both the central moments of the size distribution and its autocorrelation function. These oscillations, barely discussed in past studies, can arise as a consequence of the discrete time displacement invariance of the system with a period of one doubling time, and they do not disappear when including stochasticity on either division times or size heterogeneity on the starting population but only after inclusion of noise in either growth rate or septum position. This result illustrates the usefulness of having a solid mathematical description that explicitly incorporates the inherent stochasticity in various biological processes, both to understand the process in detail and to evaluate the effect of various sources of variability when creating simplified descriptions.

Anti-Inflammatory Mechanisms of Novel Synthetic Ruthenium Compounds

Inflammation is the primary biological reaction to induce severe infection or injury in the immune system. Control of different inflammatory cytokines, such as nitric oxide (NO), interleukins (IL), tumor necrosis factor alpha-(TNF-α), noncytokine mediator, prostaglandin E2 (PGE2), mitogen activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB), facilitates anti-inflammatory effect of different substances. Coordination metal complexes have been applied as metallo-drugs. Several metal complexes have found to possess potent biological activities, especially anticancer, cardioprotective, chondroprotective and anti-parasitosis activities. Among the metallo drugs, ruthenium-based (Ru) complexes have paid much attention in clinical applications. Despite the kinetic nature of Ru complexes is similar to platinum in terms of cell division events, their toxic effect is lower than that of cisplatin. This paper reviews the anti-inflammatory effect of novel synthetic Ru complexes with potential molecular mechanisms that are actively involved.

The modified mitochondrial outer membrane carrier MTCH2 links mitochondrial fusion to lipogenesis.

Mitochondrial function is integrated with cellular status through the regulation of opposing mitochondrial fusion and division events. Here we uncover a link between mitochondrial dynamics and lipid metabolism by examining the cellular role of mitochondrial carrier homologue 2 (MTCH2). MTCH2 is a modified outer mitochondrial membrane carrier protein implicated in intrinsic cell death and in the in vivo regulation of fatty acid metabolism. Our data indicate that MTCH2 is a selective effector of starvation-induced mitochondrial hyperfusion, a cytoprotective response to nutrient deprivation. We find that MTCH2 stimulates mitochondrial fusion in a manner dependent on the bioactive lipogenesis intermediate lysophosphatidic acid. We propose that MTCH2 monitors flux through the lipogenesis pathway and transmits this information to the mitochondrial fusion machinery to promote mitochondrial elongation, enhanced energy production, and cellular survival under homeostatic and starvation conditions. These findings will help resolve the roles of MTCH2 and mitochondria in tissue-specific lipid metabolism in animals.

Dual role of Fam208a during zygotic cleavage and early embryonic development

Maintenance of genome stability is essential for every living cell as genetic information is repeatedly challenged during DNA replication in each cell division event. Errors, defects, delays, and mistakes that arise during mitosis or meiosis lead to an activation of DNA repair processes and in case of their failure, programmed cell death, i.e. apoptosis, could be initiated. Fam208a is a protein whose importance in heterochromatin maintenance has been described recently. In this work, we describe the crucial role of Fam208a in sustaining genome stability during cellular division.The targeted depletion of Fam208a in mice using CRISPR/Cas9 led to embryonic lethality before E12.5. We also used the siRNA approach to downregulate Fam208a in zygotes to avoid the influence of maternal RNA in the early stages of development. This early downregulation increased arresting of the embryonal development at the two-cell stage and the occurrence of multipolar spindles formation. To investigate this further, we used the yeast two-hybrid (Y2H) system and identified new putative interaction partners Gpsm2, Svil, and Itgb3bp. Their co-expression with Fam208a was assessed by RT-qPCR profiling and in situ hybridization [1] in multiple murine tissues. Based on these results we proposed that Fam208a functions within the HUSH complex by interaction with Mphosph8 as these proteins are not only able to physically interact but also co-localise. We are bringing new evidence that Fam208a is a multi-interacting protein affecting genome stability on the cell division level at the earliest stages of development and by interaction with methylation complex in adult tissues.In addition to its epigenetic functions, Fam208a appears to have an important role in the zygotic division, possibly via interaction with newly identified putative partners Gpsm2, Svil, and Itgb3bp.

Prognostic Significance of KIF11 and KIF14 Expression in Pancreatic Adenocarcinoma.

Simple SummaryPrognostic markers for survival stratification of patients with pancreatic adenocarcinoma (PAC) are missing yet. Therefore, the primary aim of this study was to assess the expression, clinical associations, and survival implications of KIF11 and KIF14 in PACs. In addition, the genes co-expressed with KIF11 or KIF14 were predicted and functionally annotated. Herein, we found that the expression patterns of KIF11 and KIF14 alter significantly in PACs, at both protein and mRNA levels, and this may be harnessed for patient prognosis. KIF11 and KIF14 could be defined as positive prognostic biomarkers based on the protein-based immunohistochemistry data, while they were associated with adverse prognosis based on the transcriptomic data. We also captured a five-gene prognostic signature and the biology associated with it. The findings of the present study suggest that KIF11 or KIF14 proteins, as well as a new five-gene panel, may serve as potentially useful prognostic biomarkers for PAC.Available biomarkers for pancreatic adenocarcinoma (PAC) are inadequate to guide individual patient prognosis or therapy. Therefore, herein we aimed to verify the hypothesis that differences in the expression of KIF11 and KIF14, i.e., molecular motor proteins being primarily implicated in cell division events could account for the differences in the clinical outcome of PAC patients. In-house immunohistochemistry was used to evaluate the protein expressions of KIF11 and KIF14 in PAC, whereas RNA-seq datasets providing transcript expression data were obtained from public sources. IHC and mRNA results were correlated with clinicopathological features and overall survival (OS). Furthermore, the genes co-expressed with KIF11 or KIF14 were predicted and functionally annotated. In our series, malignant ducts displayed more intense but less abundant KIF11 staining than normal-appearing ducts. The former was also true for KIF14, whereas the prevalence of positive staining was similar in tumor and normal adjacent tissues. Based on categorical immunoreactive scores, we found KIF11 and KIF14 to be frequently downregulated or upregulated in PAC cases, respectively, and those with elevated levels of either protein, or both together, were associated with better prognosis. Specifically, we provide the first evidence that KIF11 or KIF14 proteins can robustly discriminate between patients with better and worse OS, independently of other relevant clinical risk factors. In turn, mRNA levels of KIF11 and KIF14 were markedly elevated in tumor tissues compared to normal tissues, and this coincided with adverse prognosis, even after adjusting for multiple confounders. Tumors with low predicted KIF11 or KIF14 expression were seen to have enrichment for circadian clock, whereas those with high levels were enriched for the genomic instability-related gene set. KIF11 and KIF14 were strongly correlated with one another, and CEP55, ASPM, and GAMT were identified as the main hub genes. Importantly, the combined expression of these five genes emerged as the most powerful independent prognostic indicator associated with poor survival outcome compared to classical clinicopathological factors and any marker alone. In conclusion, our study identifies novel prognostic biomarkers for PAC, which await validation.

A - 10 Concussion Rates and Sports Participation Time Loss in Sex-Comparable Middle School Sports

Abstract Objective High rates of concussion in sex-comparable sports have been reported at the high school (HS), however, research examining concussion rates and time loss, in middle school (MS) sports is limited; therefore, we investigated concussion rates and time loss (TL) in sex-comparable MS sports. Methods Concussion and athlete exposure (AE) data was collected for all MS sponsored events in a metropolitan public-school division between 2015/16–2019/20. AE was defined as one athlete participating in one sport-event. TL was defined as the number of days between the injury and return to sport dates. Injury rates (IR) per 1000 AEs with 95% confidence intervals (CI) were calculated for sex-comparable sports (baseball/softball, basketball, soccer, & track). Injury rate ratios (IRR) with 95% CIs were compared IR between sexes. CIs excluding 1.0 were considered significant. A Mann–Whitney U test compared mean TL between sexes. Results 76 concussions (IR = 0.35/1000AEs, 95%CI: 0.27–0.43) occurred across 215,074 AEs. Girls had a higher IR (0.48, 95%CI: 0.35–0.62, n = 52) than boys (0.22, 95%CI: 0.13–0.31, n = 24; IRR:2.18, 95%CI:1.34–3.53). Girls had a greater mean TL (20.27 ± 16.96 days) than boys (13.67 ± 5.66 days, U = 282.5, p = 0.04). Conclusions Within sex-comparable sports, girls had nearly twice the IR, and took nearly 7 days longer to recover than boys. IR differences between sexes in MS and HS athletes were consistent, however MS girls needed nearly one-week longer to recover than HS girls, while MS and HS boys were similar. Further inquiry into MS sport concussion rates, sex differences, and subsequent TL is warranted.

Large fluctuations in multi-scale modeling for rest hematopoiesis.

Hematopoiesis is a biological phenomenon (process) of production of mature blood cells by cellular differentiation. It is based on amplification steps due to an interplay between renewal and differentiation in the successive cell types from stem cells to mature blood cells. We will study this mechanism with a stochastic point of view to explain unexpected fluctuations on the mature blood cell number, as surprisingly observed by biologists and medical doctors in a rest hematopoiesis. We consider three cell types: stem cells, progenitors and mature blood cells. Each cell type is characterized by its own dynamics parameters, the division rate and the renewal and differentiation probabilities at each division event. We model the global population dynamics by a three-dimensional stochastic decomposable branching process. We show that the amplification mechanism is given by the inverse of the small difference between the differentiation and renewal probabilities. Introducing a parameter K which scales simultaneously the size of the first component, the differentiation and renewal probabilities and the mature blood cell death rate, we describe the asymptotic behavior of the process for large K. We show that each cell type has its own size and time scales. Focusing on the third component, we prove that the mature blood cell population size, conveniently renormalized (in time and size), is expanded in an unusual way inducing large fluctuations. The proofs are based on a fine study of the different scales involved in the model and on the use of different convergence and average techniques in the proofs.

The effects of access restrictions and communication strategies for divisive environmental management

In 2018, the U.S. National Park Service announced a controversial plan to translocate 20−30 gray wolves (Canis lupus) to Isle Royale National Park to increase genetic diversity and ultimately the dwindling wolf population. Media were restricted physical access during the translocations, citing safety concerns for the wolves and management team, as well as logistical challenges because of the remoteness of the park. Given these restrictions, we used interviews and quantitative analyses of news stories and press releases to examine what communication strategies the National Park Service and its partners deployed and how access restriction affected the way news outlets covered the events. By identifying source diversity groups, we found U.S. government sources were predominately featured with few other source types included, and that coverage heavily relied on press release information. We discuss the implications of this communication strategy and potential consequences for access restrictions when covering divisive events in remote locations.

Dynamic spatiotemporal coordination of neural stem cell fate decisions occurs through local feedback in the adult vertebrate brain.

SummaryNeural stem cell (NSC) populations persist in the adult vertebrate brain over a lifetime, and their homeostasis is controlled at the population level through unknown mechanisms. Here, we combine dynamic imaging of entire NSC populations in their in vivo niche over several weeks with pharmacological manipulations, mathematical modeling, and spatial statistics and demonstrate that NSCs use spatiotemporally resolved local feedback signals to coordinate their decision to divide in adult zebrafish brains. These involve Notch-mediated short-range inhibition from transient neural progenitors and a dispersion effect from the dividing NSCs themselves exerted with a delay of 9–12 days. Simulations from a stochastic NSC lattice model capturing these interactions demonstrate that these signals are linked by lineage progression and control the spatiotemporal distribution of output neurons. These results highlight how local and temporally delayed interactions occurring between brain germinal cells generate self-propagating dynamics that maintain NSC population homeostasis and coordinate specific spatiotemporal correlations.

Modeling protein concentrations in cycling cells using stochastic hybrid systems

We analyze a class of time-triggered stochastic hybrid systems where the state-space evolves as per a linear time-invariant dynamical system. This continuous-time evolution is interspersed with two kinds of stochastic resets. The first reset occurs based on an internal timer that measures the time elapsed since it last occurred. Whenever the first reset occurs, the states-space undergoes a random jump, and the timer is reset to zero. The second reset occurs based on an arbitrary timer-depended rate, and whenever this reset fires, the state-space is changed based on a given random map. We provide exact conditions for this class of systems that lead to finite statistical moments and the corresponding exact analytical expressions for the first two moments. This framework is applied to study random fluctuations in the concentration of a protein in a growing cell. In the context of this example, the timer denotes the time elapsed since the cell was born, and the cell division event (first reset) is triggered based on a timer-dependent rate. The second reset corresponds to the protein synthesis in stochastic bursts, and finally, during cell growth, protein concentration continuously decreases due to dilution. Our analysis provides closed-form formulas for the noise in the protein concentration and leads to a striking result - for a constant (timer-independent) protein synthesis rate, the noise in the protein concentration is invariant of the noise in the cell-cycle time. Finally, we provide a rigorous framework for investigating protein noise levels for different forms of timer-dependent synthesis rates, as is the case for cell-cycle regulated genes inside the cell.