50 research outputs found
Direct competition results from strong competiton for limited resource
We study a model of competition for resource through a chemostat-type model
where species consume the common resource that is constantly supplied. We
assume that the species and resources are characterized by a continuous trait.
As already proved, this model, although more complicated than the usual
Lotka-Volterra direct competition model, describes competitive interactions
leading to concentrated distributions of species in continuous trait space.
Here we assume a very fast dynamics for the supply of the resource and a fast
dynamics for death and uptake rates. In this regime we show that factors that
are independent of the resource competition become as important as the
competition efficiency and that the direct competition model is a good
approximation of the chemostat. Assuming these two timescales allows us to
establish a mathematically rigorous proof showing that our resource-competition
model with continuous traits converges to a direct competition model. We also
show that the two timescales assumption is required to mathematically justify
the corresponding classic result on a model consisting of only finite number of
species and resources (MacArthur, R. Theor. Popul. Biol. 1970:1, 1-11). This is
performed through asymptotic analysis, introducing different scales for the
resource renewal rate and the uptake rate. The mathematical difficulty relies
in a possible initial layer for the resource dynamics. The chemostat model
comes with a global convex Lyapunov functional. We show that the particular
form of the competition kernel derived from the uptake kernel, satisfies a
positivity property which is known to be necessary for the direct competition
model to enjoy the related Lyapunov functional
Structured models of cell migration incorporating molecular binding processes
The dynamic interplay between collective cell movement and the various
molecules involved in the accompanying cell signalling mechanisms plays a
crucial role in many biological processes including normal tissue development
and pathological scenarios such as wound healing and cancer. Information about
the various structures embedded within these processes allows a detailed
exploration of the binding of molecular species to cell-surface receptors
within the evolving cell population. In this paper we establish a general
spatio-temporal-structural framework that enables the description of molecular
binding to cell membranes coupled with the cell population dynamics. We first
provide a general theoretical description for this approach and then illustrate
it with two examples arising from cancer invasion
A note on blow-up of solutions for the nonlocal quasilinear parabolic equation with positive initial energy
Tobacco Upregulates P. gingivalis Fimbrial Proteins Which Induce TLR2 Hyposensitivity
Tobacco smokers are more susceptible to periodontitis than non-smokers but exhibit reduced signs of clinical inflammation. The underlying mechanisms are unknown. We have previously shown that cigarette smoke extract (CSE) represents an environmental stress to which P. gingivalis adapts by altering the expression of several virulence factors - including major and minor fimbrial antigens (FimA and Mfa1, respectively) and capsule - concomitant with a reduced pro-inflammatory potential of intact P. gingivalis.We hypothesized that CSE-regulation of capsule and fimbrial genes is reflected at the ultrastructural and functional levels, alters the nature of host-pathogen interactions, and contributes to the reduced pro- inflammatory potential of smoke exposed P. gingivalis. CSE induced ultrastructural alterations were determined by electron microscopy, confirmed by Western blot and physiological consequences studied in open-flow biofilms. Inflammatory profiling of specific CSE-dysregulated proteins, rFimA and rMfa1, was determined by quantifying cytokine induction in primary human innate and OBA-9 cells. CSE up-regulates P. gingivalis FimA at the protein level, suppresses the production of capsular polysaccharides at the ultrastructural level, and creates conditions that promote biofilm formation. We further show that while FimA is recognized by TLR2/6, it has only minimal inflammatory activity in several cell types. Furthermore, FimA stimulation chronically abrogates the pro-inflammatory response to subsequent TLR2 stimulation by other TLR-2-specific agonists (Pam3CSK4, FSL, Mfa1) in an IkappaBalpha- and IRAK-1-dependent manner.These studies provide some of the first information to explain, mechanistically, how tobacco smoke changes the P. gingivalis phenotype in a manner likely to promote P. gingivalis colonization and infection while simultaneously reducing the host response to this major mucosal pathogen
Computational Approaches and Analysis for a Spatio-Structural-Temporal Invasive Carcinoma Model
Spatio-temporal models have long been used to describe biological systems of cancer, but it has not been until very recently that increased attention has been paid to structural dynamics of the interaction between cancer populations and the molecular mechanisms associated with local invasion. One system that is of particular interest is that of the urokinase plasminogen activator (uPA) wherein uPA binds uPA receptors on the cancer cell surface, allowing plasminogen to be cleaved into plasmin, which degrades the extracellular matrix and this way leads to enhanced cancer cell migration. In this paper, we develop a novel numerical approach and associated analysis for spatio-structuro-temporal modelling of the uPA system for up to two-spatial and two-structural dimensions. This is accompanied by analytical exploration of the numerical techniques used in simulating this system, with special consideration being given to the proof of stability within numerical regimes encapsulating a central differences approach to approximating numerical gradients. The stability analysis performed here reveals instabilities induced by the coupling of the structural binding and proliferative processes. The numerical results expound how the uPA system aids the tumour in invading the local stroma, whilst the inhibitor to this system may impede this behaviour and encourage a more sporadic pattern of invasion.PostprintPeer reviewe
Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/ mTOR axis in metastatic pheochromocytoma/ paraganglioma
Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients’ liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67·10-18), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients’ management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors
Safety and tolerability of antidepressant co-treatment in acute major depressive disorder: results from a systematic review and exploratory meta-analysis
INTRODUCTION: Although antidepressant (AD) monotherapy is recommended first-line for major depressive disorder (MDD), AD + AD co-treatment is common. AREAS COVERED: We conducted the first systematic review searching PubMed/MEDLINE/PsycInfo/Embase from database inception until 1 June 2015 for acute randomized trials in \u3e/= 20 adults with MDD comparing AD monotherapy with AD + AD co-treatment that reported quantitative data on adverse events (AEs). Meta-analyzing 23 studies (n = 2435, duration = 6.6 weeks) AD monotherapy and AD + AD co-treatment were similar regarding intolerability-related discontinuation (risk ratio [RR] = 1.38, 95% CI = 0.89 - 1.10) and frequency of \u3e/= 1 AE (RR = 1.19, 95% CI = 0.95 - 1.49). Nevertheless, AD + AD co-treatment was associated with significantly greater burden regarding 4/25 AEs (tremor: RR = 1.55, 95% CI = 1.01 - 2.38; sweating: RR = 1.95, 95% CI = 1.13 -3.38, \u3e/= 7% weight gain: RR = 3.15, 95% CI = 1.34 - 7.41; weight gain = 2.17, 95% CI = 0.71 - 3.63 kg), but not more CNS, gastrointestinal, sexual or alertness-related AEs. However, 11/25 AEs (44.0%) were reported in only 1 - 2 studies. Adding noradrenergic and specific serotonergic antidepressants (NaSSA) or tricyclic antidepressants (TCA) to selective serotonin reuptake inhibitors (SSRIs) was specifically associated with more AEs. EXPERT OPINION: The potential for increased AEs with AD + AD co-treatment needs to be considered vis-a-vis unclear efficacy benefits of this strategy. In particular, NaSSAs and TCAs should be added to SSRIs with caution. Clearly, more data on side-effect burden of AD + AD co-treatment are needed
Plasma metanephrines and prospective prediction of tumor location, size and mutation type in patients with pheochromocytoma and paraganglioma
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Symmetry and attractors: The case N ≤ 4.
In the previous chapter, we showed that nonnegative solutions of elliptic equations in “asymptotically symmetric” domains are “asymptotically symmetric” as well (see Theorem 3.3 ). However, in order to prove Theorem 3.3, we imposed a restriction on the dimension (less or equal 3) of the underlying domain, which was crucial for our proof. The goal of this chapter is to extend Theorem 3.3 for higher dimensions