How In-Silico Experiments Can Help Drug-Discovery: The Glutamatergic Synapse as an Example of Application

This work aims to show on a very concrete example that simulations (In-Silico experiments) can help drug discovery process and therapeutic strategies search. Such an approach must be based, to reflect the complexity of physiological systems, on a modeling methodology taking into account several organization levels and time scales, and focused on physiological functions and their interactions. First, we present shortly a modeling framework built on top of a physiological systems theory. Then, we apply this approach to model the memory induction at synaptic level where the described system includes some cellular and molecular mechanisms. Finally we propose an application of \u27in silico\u27 experiments in order to exhibit some synergistic effects of biochemical mechanisms and to suggest new combinatorial therapeutics

A hierarchical modeling approach of Hippocampus local circuit

The modeling and simulation of a realistic nervous tissue are difficult because of the number of implied cell types (neuronal and glial), the topology of the networks, and the various heterogeneous molecular mechanisms. The MTIP (Mathematical Theory of Integrative Physiology) is used as a new modeling approach based on a representation in terms of functional interactions and a formalism (S-Propagator) related to n-level field theory. This work presents the passage from a theoretical description of the biological system to a computing implementation in the general case. The specific case of the hippocampus is presented, as well as how a drug allows learning and memory improvement in the local circuit of the CA1 area of the hippocampus. This in silico result is used to experimentally predict the drug effect in vitro to confirm the accuracy of MTIP

The Mathematical Theory of Integrative Physiology: Application to hippocampus for drug discovery

The modeling and the simulation of biological structure needs a united formalism for all parts of a living system. For this purpose the MTIP (Mathematical Theory of Integrative Physiology) has been developed, by Pr Gilbert Chauvet, to offer an integrated description of a living system. In this paper we will present mainly the passage from a mathematical view of a living subsystem (CA1 circuit of the hippocampus) to its computational implementation and the development of the simulator that goes with in the aim to use and validate the MTIP

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None