135 research outputs found
Effect of Dedifferentiation on Time to Mutation Acquisition in Stem Cell-Driven Cancers
Accumulating evidence suggests that many tumors have a hierarchical
organization, with the bulk of the tumor composed of relatively differentiated
short-lived progenitor cells that are maintained by a small population of
undifferentiated long-lived cancer stem cells. It is unclear, however, whether
cancer stem cells originate from normal stem cells or from dedifferentiated
progenitor cells. To address this, we mathematically modeled the effect of
dedifferentiation on carcinogenesis. We considered a hybrid
stochastic-deterministic model of mutation accumulation in both stem cells and
progenitors, including dedifferentiation of progenitor cells to a stem
cell-like state. We performed exact computer simulations of the emergence of
tumor subpopulations with two mutations, and we derived semi-analytical
estimates for the waiting time distribution to fixation. Our results suggest
that dedifferentiation may play an important role in carcinogenesis, depending
on how stem cell homeostasis is maintained. If the stem cell population size is
held strictly constant (due to all divisions being asymmetric), we found that
dedifferentiation acts like a positive selective force in the stem cell
population and thus speeds carcinogenesis. If the stem cell population size is
allowed to vary stochastically with density-dependent reproduction rates
(allowing both symmetric and asymmetric divisions), we found that
dedifferentiation beyond a critical threshold leads to exponential growth of
the stem cell population. Thus, dedifferentiation may play a crucial role, the
common modeling assumption of constant stem cell population size may not be
adequate, and further progress in understanding carcinogenesis demands a more
detailed mechanistic understanding of stem cell homeostasis
PRIORITY OF CONSTITUTION AND POSITION OF INTERNATIONAL TREATIES IN LEGAL SOURCES SYSTEM
DaudzÄs valstÄ«s ir noteikts, ka KonstitĆ«cija ir nozÄ«mÄ«gÄkais tiesÄ«bu akts un starptautiskÄs saistÄ«bas nevar ietekmÄt KonstitĆ«cijas demokrÄtisko pamatu. CilvÄktiesÄ«bu garantÄĆĄana ir demokrÄtiskas valsts pamatprincips, kÄ arÄ« tiesiskas valsts elements. CilvÄka tiesÄ«bu un pamatbrÄ«vÄ«bu aizsardzÄ«bas konvencijas preambulÄ noteikts, ka ĆĄÄ«s pamatbrÄ«vÄ«bas vislabÄk var nodroĆĄinÄt ar efektÄ«vas politiskas demokrÄtijas palÄ«dzÄ«bu. AnalizÄjot Satversmes tiesas un Somijas AugstÄkÄs tiesas spriedumus, secinÄts, ka KonstitĆ«cijai ir prioritÄra nozÄ«me, ja CilvÄka tiesÄ«bu un pamatbrÄ«vÄ«bu aizsardzÄ«bas konvencijas normu interpretÄcijas gaitÄ raduĆĄÄs konstitucionÄli - tiesiskas kolÄ«zija
COVID-19 Pandemic and Changes to Finlandâs Legislation in Line with the WHO Guidelines
The article analyses new legislative amendments in Finland, including an interim amendment to the Infectious Diseases Act, which aims to protect the life and health of clients and patients using social and medical services. The rapid spread of the number of cases of coronavirus infection in Finland, including the new Omicron strain, required urgent measures and new amendments to the legislation. Therefore, in the context of the overall fight against the coronavirus pandemic in the world, these provisions of the Finnish Constitution are a transition from the absolute priority of universally recognised norms of international law to the priority of the Basic Law, subject to the condition of the inadmissibility of guaranteed restriction of human rights. Finlandâs desire to comply with the global integration processes in the context of persisting risks of the spread of coronavirus infection has led to digital harmonisation of legislation and legal norms in accordance with the principles of international law. The amendments to Finnish legislation were based on the enshrined provisions of the Constitution and the existing international legal framework, considering possibilities for responding to pandemic and transboundary emergencies in accordance with WHO guidelines
Modelling Cell Polarization Driven by Synthetic Spatially Graded Rac Activation
The small GTPase Rac is known to be an important regulator of cell polarization, cytoskeletal reorganization, and motility of mammalian cells. In recent microfluidic experiments, HeLa cells endowed with appropriate constructs were subjected to gradients of the small molecule rapamycin leading to synthetic membrane recruitment of a Rac activator and direct graded activation of membrane-associated Rac. Rac activation could thus be triggered independent of upstream signaling mechanisms otherwise responsible for transducing activating gradient signals. The response of the cells to such stimulation depended on exceeding a threshold of activated Rac. Here we develop a minimal reaction-diffusion model for the GTPase network alone and for GTPase-phosphoinositide crosstalk that is consistent with experimental observations for the polarization of the cells. The modeling suggests that mutual inhibition is a more likely mode of cell polarization than positive feedback of Rac onto its own activation. We use a new analytical tool, Local Perturbation Analysis, to approximate the partial differential equations by ordinary differential equations for local and global variables. This method helps to analyze the parameter space and behaviour of the proposed models. The models and experiments suggest that (1) spatially uniform stimulation serves to sensitize a cell to applied gradients. (2) Feedback between phosphoinositides and Rho GTPases sensitizes a cell. (3) Cell lengthening/flattening accompanying polarization can increase the sensitivity of a cell and stabilize an otherwise unstable polarization
Low molecular weight organic acid salts, markers of old fungi activity in wall paintings
Micro-Infrared Spectroscopy (mSR-FTIR) and X-ray diffraction (mSR-XRD) with synchrotron light, Gas
Chromatography/Mass Spectrometry (CG/MS), Optical Microscopy (OM) and Scanning Electron
Microscopy (SEM/EDS) were used to identify and obtain the distribution of complex mixtures of calcium
salts of low molecular weight organic acids (LMWOA) in micro-layered micro-samples. Filamentous fungi
produce LMWOA that can react with metal cations producing stable salts. These substances were found
in the dark spots covering the surfaces of Saint Michael's Chapel wall paintings of the Royal Monastery of
Pedralbes in Barcelona linking them to old fungi activity. The presence of glycerol likewise related to the
fungi activity is also identified in the layers.Postprint (author's final draft
Best Practices for Virtual Care: A Consensus Statement From the Canadian Rheumatology Association
Objective. To develop best practice statements for the provision of virtual care in adult and pediatric rheumatology for the Canadian Rheumatology Association\u27s (CRA) Telehealth Working Group (TWG). Methods. Four members of the TWG representing adult, pediatric, university-based, and community rheumatology practices defined the scope of the project. A rapid literature review of existing systematic reviews, policy documents, and published literature and abstracts on the topic was conducted between April and May 2021. The review informed a candidate set of 7 statements and a supporting document. The statements were submitted to a 3-round (R) modified Delphi process with 22 panelists recruited through the CRA and patient advocacy organizations. Panelists rated the importance and feasibility of the statements on a Likert scale of 1-9. Statements with final median ratings between 7-9 with no disagreement were retained in the final set. Results. Twenty-one (95%) panelists participated in R1, 15 (71%) in R2, and 18 (82%) in R3. All but 1 statement met inclusion criteria during R1. Revisions were made to 5/7 statements following R2 and an additional statement was added. All statements met inclusion criteria following R3. The statements addressed the following themes in the provision of virtual care: adherence to existing standards and regulations, appropriateness, consent, physical examination, patient-reported outcomes, use in addition to in-person visits, and complex comanagement of disease. Conclusion. The best practice statements represent a starting point for advancing virtual care in rheumatology. Future educational efforts to help implement these best practices and research to address identified knowledge gaps are planned
Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches.
Dynamic interactions between RhoA and Rac1, members of the Rho small GTPase family, play a vital role in the control of cell migration. Using predictive mathematical modeling, mass spectrometry-based quantitation of network components, and experimental validation in MDA-MB-231 mesenchymal breast cancer cells, we show that a network containing Rac1, RhoA, and PAK family kinases can produce bistable, switch-like responses to a graded PAK inhibition. Using a small chemical inhibitor of PAK, we demonstrate that cellular RhoA and Rac1 activation levels respond in a history-dependent, bistable manner to PAK inhibition. Consequently, we show that downstream signaling, actin dynamics, and cell migration also behave in a bistable fashion, displaying switches and hysteresis in response to PAK inhibition. Our results demonstrate that PAK is a critical component in the Rac1-RhoA inhibitory crosstalk that governs bistable GTPase activity, cell morphology, and cell migration switches
A Density-Dependent Switch Drives Stochastic Clustering and Polarization of Signaling Molecules
Positive feedback plays a key role in the ability of signaling molecules to form highly localized clusters in the membrane or cytosol of cells. Such clustering can occur in the absence of localizing mechanisms such as pre-existing spatial cues, diffusional barriers, or molecular cross-linking. What prevents positive feedback from amplifying inevitable biological noise when an un-clustered âoffâ state is desired? And, what limits the spread of clusters when an âonâ state is desired? Here, we show that a minimal positive feedback circuit provides the general principle for both suppressing and amplifying noise: below a critical density of signaling molecules, clustering switches off; above this threshold, highly localized clusters are recurrently generated. Clustering occurs only in the stochastic regime, suggesting that finite sizes of molecular populations cannot be ignored in signal transduction networks. The emergence of a dominant cluster for finite numbers of molecules is partly a phenomenon of random sampling, analogous to the fixation or loss of neutral mutations in finite populations. We refer to our model as the âneutral drift polarity model.â Regulating the density of signaling molecules provides a simple mechanism for a positive feedback circuit to robustly switch between clustered and un-clustered states. The intrinsic ability of positive feedback both to create and suppress clustering is a general mechanism that could operate within diverse biological networks to create dynamic spatial organization
Positional Information Generated by Spatially Distributed Signaling Cascades
The temporal and stationary behavior of protein modification cascades has been extensively studied, yet little is known about the spatial aspects of signal propagation. We have previously shown that the spatial separation of opposing enzymes, such as a kinase and a phosphatase, creates signaling activity gradients. Here we show under what conditions signals stall in the space or robustly propagate through spatially distributed signaling cascades. Robust signal propagation results in activity gradients with long plateaus, which abruptly decay at successive spatial locations. We derive an approximate analytical solution that relates the maximal amplitude and propagation length of each activation profile with the cascade level, protein diffusivity, and the ratio of the opposing enzyme activities. The control of the spatial signal propagation appears to be very different from the control of transient temporal responses for spatially homogenous cascades. For spatially distributed cascades where activating and deactivating enzymes operate far from saturation, the ratio of the opposing enzyme activities is shown to be a key parameter controlling signal propagation. The signaling gradients characteristic for robust signal propagation exemplify a pattern formation mechanism that generates precise spatial guidance for multiple cellular processes and conveys information about the cell size to the nucleus
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