435 research outputs found
Multiple verification in computational modeling of bone pathologies
We introduce a model checking approach to diagnose the emerging of bone
pathologies. The implementation of a new model of bone remodeling in PRISM has
led to an interesting characterization of osteoporosis as a defective bone
remodeling dynamics with respect to other bone pathologies. Our approach allows
to derive three types of model checking-based diagnostic estimators. The first
diagnostic measure focuses on the level of bone mineral density, which is
currently used in medical practice. In addition, we have introduced a novel
diagnostic estimator which uses the full patient clinical record, here
simulated using the modeling framework. This estimator detects rapid (months)
negative changes in bone mineral density. Independently of the actual bone
mineral density, when the decrease occurs rapidly it is important to alarm the
patient and monitor him/her more closely to detect insurgence of other bone
co-morbidities. A third estimator takes into account the variance of the bone
density, which could address the investigation of metabolic syndromes, diabetes
and cancer. Our implementation could make use of different logical combinations
of these statistical estimators and could incorporate other biomarkers for
other systemic co-morbidities (for example diabetes and thalassemia). We are
delighted to report that the combination of stochastic modeling with formal
methods motivate new diagnostic framework for complex pathologies. In
particular our approach takes into consideration important properties of
biosystems such as multiscale and self-adaptiveness. The multi-diagnosis could
be further expanded, inching towards the complexity of human diseases. Finally,
we briefly introduce self-adaptiveness in formal methods which is a key
property in the regulative mechanisms of biological systems and well known in
other mathematical and engineering areas.Comment: In Proceedings CompMod 2011, arXiv:1109.104
Embryonic stem cell-derived CD166+ precursors develop into fully functional sinoatrial-like cells
Rationale: A cell-based biological pacemaker is based on the differentiation of stem cells and the selection of a population displaying the molecular and functional properties of native sinoatrial node (SAN) cardiomyocytes. So far, such selection has been hampered by the lack of proper markers. CD166 is specifically but transiently expressed in the mouse heart tube and sinus venosus, the prospective SAN.
Objective: We have explored the possibility of using CD166 expression for isolating SAN progenitors from differentiating embryonic stem cells.
Methods and Results: We found that in embryonic day 10.5 mouse hearts, CD166 and HCN4, markers of the pacemaker tissue, are coexpressed. Sorting embryonic stem cells for CD166 expression at differentiation day 8 selects a population of pacemaker precursors. CD166(+) cells express high levels of genes involved in SAN development (Tbx18, Tbx3, Isl-1, Shox2) and function (Cx30.2, HCN4, HCN1, CaV1.3) and low levels of ventricular genes (Cx43, Kv4.2, HCN2, Nkx2.5). In culture, CD166(+) cells form an autorhythmic syncytium composed of cells morphologically similar to and with the electrophysiological properties of murine SAN myocytes. Isoproterenol increases (+57%) and acetylcholine decreases (-23%) the beating rate of CD166-selected cells, which express the -adrenergic and muscarinic receptors. In cocultures, CD166-selected cells are able to pace neonatal ventricular myocytes at a rate faster than their own. Furthermore, CD166(+) cells have lost pluripotency genes and do not form teratomas in vivo.
Conclusions: We demonstrated for the first time the isolation of a nonteratogenic population of cardiac precursors able to mature and form a fully functional SAN-like tissue
Generation of human induced pluripotent stem cells (EURACi001-A, EURACi002-A, EURACi003-A) from peripheral blood mononuclear cells of three patients carrying mutations in the CAV3 gene
Caveolinopathies are a heterogeneous family of genetic pathologies arising from alterations of the caveolin-3 gene (CAV3), encoding for the isoform specifically constituting muscle caveolae. Here, by reprogramming peripheral blood mononuclear cells, we report the generation of induced pluripotent stem cells (iPSCs) from three patients carrying the ΔYTT deletion, T78K and W101C missense mutations in caveolin-3. iPSCs displayed normal karyotypes and all the features of pluripotent stem cells in terms of morphology, specific marker expression and ability to differentiate in vitro into the three germ layers. These lines thus represent a human cellular model to study the molecular basis of caveolinopathies
An Approach to the Bio-Inspired Control of Self-reconfigurable Robots
Self-reconfigurable robots are robots built by modules which
can move in relationship to each other. This ability of changing its physical
form provides the robots a high level of adaptability and robustness.
Given an initial configuration and a goal configuration of the robot, the
problem of self-regulation consists on finding a sequence of module moves
that will reconfigure the robot from the initial configuration to the goal
configuration. In this paper, we use a bio-inspired method for studying
this problem which combines a cluster-flow locomotion based on cellular
automata together with a decentralized local representation of the
spatial geometry based on membrane computing ideas. A promising 3D
software simulation and a 2D hardware experiment are also presented.National Natural Science Foundation of China No. 6167313
Multiscale Bone Remodelling with Spatial P Systems
Many biological phenomena are inherently multiscale, i.e. they are
characterized by interactions involving different spatial and temporal scales
simultaneously. Though several approaches have been proposed to provide
"multilayer" models, only Complex Automata, derived from Cellular Automata,
naturally embed spatial information and realize multiscaling with
well-established inter-scale integration schemas. Spatial P systems, a variant
of P systems in which a more geometric concept of space has been added, have
several characteristics in common with Cellular Automata. We propose such a
formalism as a basis to rephrase the Complex Automata multiscaling approach
and, in this perspective, provide a 2-scale Spatial P system describing bone
remodelling. The proposed model not only results to be highly faithful and
expressive in a multiscale scenario, but also highlights the need of a deep and
formal expressiveness study involving Complex Automata, Spatial P systems and
other promising multiscale approaches, such as our shape-based one already
resulted to be highly faithful.Comment: In Proceedings MeCBIC 2010, arXiv:1011.005
Identification of the Molecular Site of Ivabradine Binding to HCN4 Channels
Ivabradine is a specific heart rate-reducing agent approved as a treatment of chronic stable angina. Its mode of action involves a selective and specific block of HCN channels, the molecular components of sinoatrial "funny" (f)-channels. Different studies suggest that the binding site of ivabradine is located in the inner vestibule of HCN channels, but the molecular details of ivabradine binding are unknown. We thus sought to investigate by mutagenesis and in silico analysis which residues of the HCN4 channel, the HCN isoform expressed in the sinoatrial node, are involved in the binding of ivabradine. Using homology modeling, we verified the presence of an inner cavity below the channel pore and identified residues lining the cavity; these residues were replaced with alanine (or valine) either alone or in combination, and WT and mutant channels were expressed in HEK293 cells. Comparison of the block efficiency of mutant vs WT channels, measured by patch-clamp, revealed that residues Y506, F509 and I510 are involved in ivabradine binding. For each mutant channel, docking simulations correctly explain the reduced block efficiency in terms of proportionally reduced affinity for ivabradine binding. In summary our study shows that ivabradine occupies a cavity below the channel pore, and identifies specific residues facing this cavity that interact and stabilize the ivabradine molecule. This study provides an interpretation of known properties of f/HCN4 channel block by ivabradine such as the "open channel block", the current-dependence of block and the property of "trapping" of drug molecules in the closed configuration
A Possible Outbreak by Serratia Marcescens: Genetic Relatedness between Clinical and Environmental Strains
Serratia marcescens (SM) is a Gram-negative bacterium that is frequently found in the environment. Since 1913, when its pathogenicity was first demonstrated, the number of infections caused by SM has increased. There is ample evidence that SM causes nosocomial infections in immunocompromised or critically ill patients admitted to the intensive care units (ICUs), but also in newborns admitted to neonatal ICUs (NICUs). In this study, we evaluated the possible genetic correlation by PFGE between clinical and environmental SM strains from NICU and ICU and compared the genetic profile of clinical strains with strains isolated from patients admitted to other wards of the same hospital. We found distinct clonally related groups of SM strains circulating among different wards of a large university hospital. In particular, the clonal relationship between clinical and environmental strains in NICU and ICU 1 was highlighted. The identification of clonal relationships between clinical and environmental strains in the wards allowed identification of the epidemic and rapid implementation of adequate measures to stop the spread of SM
Norovirus gastroenteritis general outbreak associated with raw shellfish consumption in South Italy
BACKGROUND: Despite Noroviruses (NV, previously "Norwalk-like viruses") being a leading cause of acute gastroenteritis outbreaks, the impact of NV infection is at present unknown and little information is available about strains circulating in Italy. In April 2002 an outbreak of gastroenteritis occurred in the province of Bari (South-east Italy), involving several households. METHODS: A retrospective cohort study was performed in order to assess risk factors associated with illness. All households where a case occurred were included in the study. Faecal specimens were collected from ill individuals. NV-specific RT-PCR was performed. Eleven samples of mussels were collected from fish-markets involved in the outbreak. A nested PCR was used for mussel samples. RESULTS: One hundred and three cases, detected by means of active surveillance, met the case definition. Raw shellfish eating was the principal risk factor for the disease, as indicated by the analytic issues (Risk Ratio: 1.50; IC 95%: 1.18 – 1.89; p < 0.001). NVs were found by means of RT-PCR of all the stool specimens from the 24 patients tested. Eleven samples of shellfish from local markets were tested for the presence or NVs; six were positive by nested PCR and genotypes were related to that found in patients' stools. CONCLUSION: This is the first community outbreak caused by NVs related to sea-food consumption described in Italy. The study confirms that the present standards for human faecal contamination do not seem to be a reliable indicator of viral contaminants in mussels
Potential use of untreated wastewater for assessing COVID-19 trends in southern Italy
As a complement to clinical disease surveillance, the monitoring of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in wastewater can be used as an early warning system for impending epidemics. This study investigated the dynamics of SARS-CoV-2 in untreated wastew-ater with respect to the trend of coronavirus disease 2019 (COVID-19) prevalence in Southern Italy. A total of 210 wastewater samples were collected between May and November 2020 from 15 Apulian wastewater treatment plants (WWTP). The samples were concentrated in accordance with the stan-dard of World Health Organization (WHO, Geneva, Switzerland) procedure for Poliovirus sewage surveillance, and molecular analysis was undertaken with real-time reverse-transcription quantitative PCR (RT-(q) PCR). Viral ribonucleic acid (RNA) was found in 12.4% (26/210) of the samples. The virus concentration in the positive samples ranged from 8.8 × 102 to 6.5 × 104 genome copies/L. The receiver operating characteristic (ROC) curve modeling showed that at least 11 cases/100,000 inhabitants would occur after a wastewater sample was found to be positive for SARS-CoV-2 (sensi-tivity = 80%, specificity = 80.9%). To our knowledge, this is the first study in Italy that has applied wastewater-based epidemiology to predict COVID-19 prevalence. Further studies regarding methods that include all variables (meteorological phenomena, characteristics of the WWTP, etc.) affecting this type of wastewater surveillance data would be useful to improve data interpretation
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