scholarly journals Robustness and timing of cellular differentiation through population-based symmetry breaking

2019 ◽  
Author(s):  
Angel Stanoev ◽  
Christian Schröter ◽  
Aneta Koseska
Keyword(s):  
Symmetry Breaking ◽  
Cell Communication ◽  
Population Level ◽  
Coupled System ◽  
Cell Types ◽  
Population Based ◽  
Cell Number ◽  
Mammalian Development ◽  
Growing Cell ◽  
Inhomogeneous Solution

AbstractDuring mammalian development, cell types expressing mutually exclusive genetic markers are differentiated from a multilineage primed state. These observations have invoked single-cell multistability view as the dynamical basis of differentiation. However, the robust regulative nature of mammalian development is not captured therein. Considering the well-established role of cell-cell communication in this process, we propose a fundamentally different dynamical treatment in which cellular identities emerge and are maintained on population level, as a novel unique solution of the coupled system. Subcritical system’s organization here enables symmetry-breaking to be triggered by cell number increase in a timed, self-organized manner. Robust cell type proportions are thereby an inherent feature of the resulting inhomogeneous solution. This framework is generic, as exemplified for early embryogenesis and neurogenesis cases. Distinct from mechanisms that rely on pre-existing asymmetries, we thus demonstrate that robustness and accuracy necessarily emerge from the cooperative behaviour of growing cell populations during development.

scholarly journals Robustness and timing of cellular differentiation through population-based symmetry breaking

Development ◽  
2021 ◽  
Vol 148 (3) ◽  
pp. dev197608
Author(s):  
Angel Stanoev ◽  
Christian Schröter ◽  
Aneta Koseska
Keyword(s):  
Symmetry Breaking ◽  
Single Cell ◽  
Cell Communication ◽  
Cell Types ◽  
Cell Number ◽  
Cell Type ◽  
Inhomogeneous State ◽  
Dynamical Mechanism ◽  
Homogeneous Population ◽  
Growing Cell

ABSTRACTDuring mammalian development and homeostasis, cells often transition from a multilineage primed state to one of several differentiated cell types that are marked by the expression of mutually exclusive genetic markers. These observations have been classically explained by single-cell multistability as the dynamical basis of differentiation, where robust cell-type proportioning relies on pre-existing cell-to-cell differences. We propose a conceptually different dynamical mechanism in which cell types emerge and are maintained collectively by cell-cell communication as a novel inhomogeneous state of the coupled system. Differentiation can be triggered by cell number increase as the population grows in size, through organisation of the initial homogeneous population before the symmetry-breaking bifurcation point. Robust proportioning and reliable recovery of the differentiated cell types following a perturbation is an inherent feature of the inhomogeneous state that is collectively maintained. This dynamical mechanism is valid for systems with steady-state or oscillatory single-cell dynamics. Therefore, our results suggest that timing and subsequent differentiation in robust cell-type proportions can emerge from the cooperative behaviour of growing cell populations during development.

scholarly journals Growth-factor-mediated coupling between lineage size and cell fate choice underlies robustness of mammalian development

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Néstor Saiz ◽  
Laura Mora-Bitria ◽  
Shahadat Rahman ◽  
Hannah George ◽  
Jeremy P Herder ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Fate ◽  
Population Level ◽  
Cell Types ◽  
Growth Factor Signaling ◽  
Cell Type ◽  
Mammalian Development ◽  
Mammalian Embryo ◽  
Precise Control

Precise control and maintenance of population size is fundamental for organismal development and homeostasis. The three cell types of the mammalian blastocyst are generated in precise proportions over a short time, suggesting a mechanism to ensure a reproducible outcome. We developed a minimal mathematical model demonstrating growth factor signaling is sufficient to guarantee this robustness and which anticipates an embryo's response to perturbations in lineage composition. Addition of lineage-restricted cells both in vivo and in silico, causes a shift of the fate of progenitors away from the supernumerary cell type, while eliminating cells using laser ablation biases the specification of progenitors toward the targeted cell type. Finally, FGF4 couples fate decisions to lineage composition through changes in local growth factor concentration, providing a basis for the regulative abilities of the early mammalian embryo whereby fate decisions are coordinated at the population level to robustly generate tissues in the right proportions.

Studying Populations of Online Communities

2019 ◽  
pp. 173-193
Author(s):  
Benjamin Mako Hill ◽  
Aaron Shaw
Keyword(s):  
Online Communities ◽  
Information Diffusion ◽  
Diffusion Processes ◽  
Empirical Studies ◽  
Population Level ◽  
Study Groups ◽  
Population Based ◽  
Large Majority ◽  
Community Processes ◽  
Published Research

While the large majority of published research on online communities consists of analyses conducted entirely within individual communities, this chapter argues for a population-based approach, in which researchers study groups of similar communities. For example, although there have been thousands of papers published about Wikipedia, a population-based approach might compare all wikis on a particular topic. Using examples from published empirical studies, the chapter describes five key benefits of this approach. First, it argues that population-level research increases the generalizability of findings. Next, it describes four processes and dynamics that are only possible to study using populations: community-level variables, information diffusion processes across communities, ecological dynamics, and multilevel community processes. The chapter concludes with a discussion of a series of limitations and challenges.

scholarly journals Prevalence and predictors of persistent HIV viremia and viral rebound following universal test and treat: a population-based study

2021 ◽  
Author(s):  
M Kate Grabowski ◽  
Eshan U Patel ◽  
Gertrude Nakigozi ◽  
Victor Ssempijja ◽  
Robert Ssekubugu ◽  
...  
Keyword(s):  
Population Level ◽  
Population Based ◽  
Sub Saharan Africa ◽  
Hiv Positive ◽  
Viral Rebound ◽  
Hiv Viral Load ◽  
Test And Treat ◽  
Universal Test ◽  
Persistent Viremia ◽  
Universal Test And Treat

Abstract Background There are limited data on individual HIV viral load (VL) trajectories at the population-level following the introduction of universal test and treat (UTT) in sub-Saharan Africa. Methods HIV VLs were assessed among HIV-positive participants at three population-based surveys in four Ugandan fishing communities surveyed between November 2011 and August 2017. The unit of analysis was a visit-pair (two consecutive person-visits), which were categorized as exhibiting durable VL suppression, new/renewed suppression, viral rebound, or persistent viremia. Adjusted relative risks (adjRRs) and 95%CIs of persistent viremia were estimated using multivariate Poisson regression. Results There were 1,346 HIV-positive participants (n=1,883 visit-pairs). The population-level prevalence of durable VL suppression increased from 29.7% to 67.9% during UTT rollout, viral rebound declined from 4.4% to 2.7%, and persistent viremia declined from 20.7% to 13.3%. Younger age (15-29 vs. 40-49 years, adjRR=1.80 [95%CI=1.19-2.71]), male sex (adjRR=2.09 [95%CI=1.47-2.95]), never being married (vs. currently married; adjRR=1.88 [95%CI=1.34-2.62]), and recent migration to the community (vs. long-term resident; adjRR=1.91 [95%CI=1.34-2.73]) were factors associated with persistent viremia. Conclusions Despite increases in durable VL suppression during roll-out of UTT in hyperendemic communities, a substantial fraction of the population, whose risk profile tended to be younger, male, and mobile, remained persistently viremic.

A population-based analysis in 375,233 cases of heart failure stages A, B and C. Real world epidemiology of prevalence and temporal trends in South-European populations

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Jimenez ◽  
M Cainzos-Achirica ◽  
D Monterde ◽  
L Garcia-Eroles ◽  
C Enjuanes ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Conditions ◽  
Temporal Trends ◽  
Population Level ◽  
Population Based ◽  
Relative Increase ◽  
Funding Source ◽  
Private Company ◽  
Healthcare Database ◽  
Evolutionary Changes

Abstract Background Prevalence of congestive heart failure (CHF) and predisposing conditions has described previously. Most of these studies evaluated centre-European or north-American populations. However, the prevalence and evolutionary changes of Heart Failure stages A, B and C has not been fully elucidated in Mediterranean cohorts. Purpose To estimate the prevalence of CHF (HF Stage C) and four additional key chronic cardiovascular, metabolic and renal conditions predisposing to the development of CHF (HF Stages A and B) at a population level in a south-European healthcare area. We analysed the evolutionary changes in the prevalence in these five conditions. Methods In a healthcare area of 1,3Millions inhabitants, we extracted health related information of all individuals ≥55 years old. We analysed data of 375,233 individuals included in the population-based healthcare database of a public Institute of Health between 2015 and 2017. The conditions of interest were CHF, chronic kidney disease (CKD), diabetes mellitus (DM), ischemic heart disease (IHD) and hypertension (HTN). Results The prevalence of chronic conditions was high, particularly of HTN (48.2–48.9%) and DM individuals (14.6–14.8%). The other conditions were less frequent, with prevalence around 2–4% for IHD, 5–9% for CKD and 2–4% for CHF (Table). However, the less frequent conditions had a striking upward trend with over 1,500 new prevalent cases per year between 2015 and 2017 for CHF (45% relative increase), more than 2,500 new prevalent cases for IHD (67% relative increase) and more than 4,000 new prevalent cases per year for CKD (44% relative increase). Conclusion In this south European cohort, there were a high prevalence of HTN and DM as risk factors and a significant trend of increasing prevalence in high cost chronic conditions such as CHF, IHD and CKD. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The present study was funded by an unrestricted research grant from Vifor Pharma.

scholarly journals Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function

2021 ◽  
Vol 22 (7) ◽  
pp. 3649
Author(s):  
Patricia Ramos-Ramírez ◽  
Omar Tliba
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Dominant Negative ◽  
Negative Effects ◽  
Independent Manner ◽  
Distinct Cell ◽  
Induced Apoptosis

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.

scholarly journals Modeling Hearing Loss Progression and Asymmetry in the Older Old: A National Population-Based Survey

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 214-215
Author(s):  
Rahul Sharma ◽  
Anil Lalwani ◽  
Justin Golub
Keyword(s):  
Hearing Loss ◽  
Pure Tone ◽  
Population Level ◽  
Population Based ◽  
National Database ◽  
Cross Sectional ◽  
Adult Lifespan ◽  
Pure Tone Average ◽  
Age Related ◽  
Public Datasets

Abstract The progression and asymmetry of age-related hearing loss has not been well characterized in those 80 years of age and older because public datasets mask upper extremes of age to protect anonymity. We aimed to model the progression and asymmetry of hearing loss in the older old using a representative, national database. This was a cross-sectional, multicentered US epidemiologic analysis using the National Health and Nutrition Examination Study (NHANES) 2005-2006, 2009-2010, and 2011-2012 cycles. Subjects included non-institutionalized, civilian adults 80 years and older (n=621). Federal security clearance was granted to access publicly-restricted age data. Outcome measures included pure-tone average air conduction thresholds and the 4-frequency pure tone average (PTA). 621 subjects were 80 years old or older (mean=84.2 years, range=80-104 years), representing 10,600,197 Americans. Hearing loss exhibited constant acceleration across the adult lifespan at a rate of 0.0052 dB/year2 (95% CI = 0.0049, 0.0055). Compounded over a lifetime, the velocity of hearing loss would increase five-fold, from 0.2 dB loss/year at age 20 to 1 dB loss/year at age 100. This model predicted mean PTA within 2 dB of accuracy for most ages between 20 and 100 years. There was no change in the asymmetry of hearing loss with increasing age over 80 years (linear regression coefficient of asymmetry over age=0.07 (95% CI=-0.01, 0.24). In conclusion, hearing loss steadily and predictably accelerates across the adult lifespan to at least age 100, becoming near-universal. These population-level statistics will guide treatment and policy recommendations for hearing health in the older old.

scholarly journals The landscape of alternative polyadenylation in single cells of the developing mouse embryo

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Vikram Agarwal ◽  
Sereno Lopez-Darwin ◽  
David R. Kelley ◽  
Jay Shendure
Keyword(s):  
Rna Binding ◽  
Developmental Stages ◽  
Single Cells ◽  
Neuronal Cell ◽  
Alternative Polyadenylation ◽  
Cell Types ◽  
Untranslated Regions ◽  
Mammalian Development ◽  
Translation Rate ◽  
Dynamic Landscape

Abstract3′ untranslated regions (3′ UTRs) post-transcriptionally regulate mRNA stability, localization, and translation rate. While 3′-UTR isoforms have been globally quantified in limited cell types using bulk measurements, their differential usage among cell types during mammalian development remains poorly characterized. In this study, we examine a dataset comprising ~2 million nuclei spanning E9.5–E13.5 of mouse embryonic development to quantify transcriptome-wide changes in alternative polyadenylation (APA). We observe a global lengthening of 3′ UTRs across embryonic stages in all cell types, although we detect shorter 3′ UTRs in hematopoietic lineages and longer 3′ UTRs in neuronal cell types within each stage. An analysis of RNA-binding protein (RBP) dynamics identifies ELAV-like family members, which are concomitantly induced in neuronal lineages and developmental stages experiencing 3′-UTR lengthening, as putative regulators of APA. By measuring 3′-UTR isoforms in an expansive single cell dataset, our work provides a transcriptome-wide and organism-wide map of the dynamic landscape of alternative polyadenylation during mammalian organogenesis.

scholarly journals Single-cell analysis reveals cell communication triggered by macrophages associated with the reduction and exhaustion of CD8+ T cells in COVID-19

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lei He ◽  
Quan Zhang ◽  
Yue Zhang ◽  
Yixian Fan ◽  
Fahu Yuan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cell Communication ◽  
Cell Types ◽  
Trial Registration ◽  
T Cell Subsets ◽  
Disease Group ◽  
Communication Analysis ◽  
Receptor Interactions

Abstract Background The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has become an ongoing pandemic. Understanding the respiratory immune microenvironment which is composed of multiple cell types, together with cell communication based on ligand–receptor interactions is important for developing vaccines, probing COVID-19 pathogenesis, and improving pandemic control measures. Methods A total of 102 consecutive hospitalized patients with confirmed COVID-19 were enrolled in this study. Clinical information, routine laboratory tests, and flow cytometry analysis data with different conditions were collected and assessed for predictive value in COVID-19 patients. Next, we analyzed public single-cell RNA-sequencing (scRNA-seq) data from bronchoalveolar lavage fluid, which offers the closest available view of immune cell heterogeneity as encountered in patients with varying severity of COVID-19. A weighting algorithm was used to calculate ligand–receptor interactions, revealing the communication potentially associated with outcomes across cell types. Finally, serum cytokines including IL6, IL1β, IL10, CXCL10, TNFα, GALECTIN-1, and IGF1 derived from patients were measured. Results Of the 102 COVID-19 patients, 42 cases (41.2%) were categorized as severe. Multivariate logistic regression analysis demonstrated that AST, D-dimer, BUN, and WBC were considered as independent risk factors for the severity of COVID-19. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe disease group were significantly lower than those in the moderate disease group. The risk model containing the above mentioned inflammatory damage parameters, and the counts of T cells, with AUROCs ranged from 0.78 to 0.87. To investigate the molecular mechanism at the cellular level, we analyzed the published scRNA-seq data and found that macrophages displayed specific functional diversity after SARS-Cov-2 infection, and the metabolic pathway activities in the identified macrophage subtypes were influenced by hypoxia status. Importantly, we described ligand–receptor interactions that are related to COVID-19 serverity involving macrophages and T cell subsets by communication analysis. Conclusions Our study showed that macrophages driving ligand–receptor crosstalk contributed to the reduction and exhaustion of CD8+ T cells. The identified crucial cytokine panel, including IL6, IL1β, IL10, CXCL10, IGF1, and GALECTIN-1, may offer the selective targets to improve the efficacy of COVID-19 therapy. Trial registration: This is a retrospective observational study without a trial registration number.

scholarly journals Extracellular Vesicles-Based Drug Delivery Systems: A New Challenge and the Exemplum of Malignant Pleural Mesothelioma

2020 ◽  
Vol 21 (15) ◽  
pp. 5432 ◽  
Author(s):  
Stefano Burgio ◽  
Leila Noori ◽  
Antonella Marino Gammazza ◽  
Claudia Campanella ◽  
Mariantonia Logozzi ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Early Diagnosis ◽  
Extracellular Vesicles ◽  
Delivery System ◽  
Malignant Pleural Mesothelioma ◽  
Cell Communication ◽  
Cell Types ◽  
Delivery Systems ◽  
Pleural Mesothelioma ◽  
Potential Use

Research for the most selective drug delivery to tumors represents a fascinating key target in science. Alongside the artificial delivery systems identified in the last decades (e.g., liposomes), a family of natural extracellular vesicles (EVs) has gained increasing focus for their potential use in delivering anticancer compounds. EVs are released by all cell types to mediate cell-to-cell communication both at the paracrine and the systemic levels, suggesting a role for them as an ideal nano-delivery system. Malignant pleural mesothelioma (MPM) stands out among currently untreatable tumors, also due to the difficulties in achieving an early diagnosis. Thus, early diagnosis and treatment of MPM are both unmet clinical needs. This review looks at indirect and direct evidence that EVs may represent both a new tool for allowing an early diagnosis of MPM and a potential new delivery system for more efficient therapeutic strategies. Since MPM is a relatively rare malignant tumor and preclinical MPM models developed to date are very few and not reliable, this review will report data obtained in other tumor types, suggesting the potential use of EVs in mesothelioma patients as well.

Sign in / Sign up

Export Citation Format

Share Document