recent theoretical approaches to minimal artificial cells

Minimal artificial cells (MACs) are self-assembled chemical systems able to mimic the behavior of living cells at a minimal level, i.e. to exhibit self-maintenance, self-reproduction and the capability of evolution. The bottom-up approach to the construction of MACs is mainly based on the encapsulation of chemical reacting systems inside lipid vesicles, i.e. chemical systems enclosed (compartmentalized) by a double-layered lipid membrane. Several researchers are currently interested in synthesizing such simple cellular models for biotechnological purposes or for investigating origin of life scenarios. Within this context, the properties of lipid vesicles (e.g., their stability, permeability, growth dynamics, potential to host reactions or undergo division processes…) play a central role, in combination with the dynamics of the encapsulated chemical or biochemical networks. Thus, from a theoretical standpoint, it is very important to develop kinetic equations in order to explore first—and specify later—the conditions that allow the robust implementation of these complex chemically reacting systems, as well as their controlled reproduction. Due to being compartmentalized in small volumes, the population of reacting molecules can be very low in terms of the number of molecules and therefore their behavior becomes highly affected by stochastic effects both in the time course of reactions and in occupancy distribution among the vesicle population. In this short review we report our mathematical approaches to model artificial cell systems in this complex scenario by giving a summary of three recent simulations studies on the topic of primitive cell (protocell) systems

The Rise of the Nested Multicompartment Model in Synthetic Cell Research

The Rise of the Nested Multicompartment Model in Synthetic Cell Researc

Measurement and Numerical Modeling of Cell-Free Protein Synthesis: Combinatorial Block-Variants of the PURE System

Protein synthesis is at the core of bottom-up construction of artificial cellular mimics. Intriguingly, several reports have revealed that when a transcription–translation (TX–TL) kit is encapsulated inside lipid vesicles (or water-in-oil droplets), high between-vesicles diversity is observed in terms of protein synthesis rate and yield. Stochastic solute partition can be a major determinant of these observations. In order to verify that the variation of TX–TL components concentration brings about a variation of produced protein rate and yield, here we directly measure the performances of the 'PURE system' TX–TL kit variants. We report and share the kinetic traces of the enhanced Green Fluorescent Protein (eGFP) synthesis in bulk aqueous phase, for 27 combinatorial block-variants. The eGFP production is a sensitive function of TX–TL components concentration in the explored concentration range. Providing direct evidence that protein synthesis yield and rate actually mirror the TX–TL composition, this study supports the above-mentioned hypothesis on stochastic solute partition, without excluding, however, the contribution of other factors (e.g., inactivation of components)

Extrinsic stochastic factors (solute partition) in gene expression inside lipid vesicles and lipid-stabilized water-in-oil droplets: a review

Abstract The encapsulation of transcription–translation (TX–TL) machinery inside lipid vesicles and water-in-oil droplets leads to the construction of cytomimetic systems (often called 'synthetic cells') for synthetic biology and origins-of-life research. A number of recent reports have shown that protein synthesis inside these microcompartments is highly diverse in terms of rate and amount of synthesized protein. Here, we discuss the role of extrinsic stochastic effects (i.e. solute partition phenomena) as relevant factors contributing to this pattern. We evidence and discuss cases where between-compartment diversity seems to exceed the expected theoretical values. The need of accurate determination of solute content inside individual vesicles or droplets is emphasized, aiming at validating or rejecting the predictions calculated from the standard fluctuations theory. At the same time, we promote the integration of experiments and stochastic modeling to reveal the details of solute encapsulation and intra-compartment reactions

Charge Recombination Kinetics of Bacterial Photosynthetic Reaction Centres Reconstituted in Liposomes: Deterministic Versus Stochastic Approach

In this theoretical work, we analyse the kinetics of charge recombination reaction after a light excitation of the Reaction Centres extracted from the photosynthetic bacterium Rhodobacter sphaeroides and reconstituted in small unilamellar phospholipid vesicles. Due to the compartmentalized nature of liposomes, vesicles may exhibit a random distribution of both ubiquinone molecules and the Reaction Centre protein complexes that can produce significant differences on the local concentrations from the average expected values. Moreover, since the amount of reacting species is very low in compartmentalized lipid systems the stochastic approach is more suitable to unveil deviations of the average time behaviour of vesicles from the deterministic time evolution

Epidemiology of atherosclerotic cardiovascular disease in polygenic hypercholesterolemia with or without high lipoprotein(a) levels

Background and aimsEpidemiology of atherosclerotic cardiovascular disease might be different in patients with polygenic hypercholesterolemia plus high levels (≥30 mg/dl) of Lp(a) (H-Lpa) than in those with polygenic hypercholesterolemia alone (H-LDL). We compared the incidence of peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CVD) in patients with H-Lpa and in those with H-LDL.MethodsRetrospective analysis of demographics, risk factors, vascular events, therapy, and lipid profile in outpatient clinical data. Inclusion criteria was adult age, diagnosis of polygenic hypercholesterolemia, and both indication and availability for Lp(a) measurement.ResultsMedical records of 258 patients with H-Lpa and 290 H-LDL were reviewed for occurrence of vascular events. The median duration of follow-up was 10 years (IQR 3–16). In spite of a similar reduction of LDL cholesterol, vascular events occurred more frequently, and approximately 7 years earlier (P = 0.024) in patients with H-Lpa than in H-LDL (HR 1.96 1.21–3.17, P = 0.006). The difference was around 10 years for acute events (TIA, Stroke, acute coronary events) and one year for chronic ones (P = 0.023 and 0.525, respectively). Occurrence of acute CAD was higher in H-Lpa men (HR 3.1, 95% CI 1.2–7.9, P = 0.007) while, among women, PAD was observed exclusively in H-Lpa subjects with smoking habits (P = 0.009).ConclusionsPatients with high Lp(a) levels suffer from a larger and earlier burden of the disease compared to those with polygenic hypercholesterolemia alone. These patients are at higher risk of CAD if they are men, and of PAD if they are women

Traces of trauma – a multivariate pattern analysis of childhood trauma, brain structure and clinical phenotypes

Background: Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. Methods: We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. Results: We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. Conclusions: Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research

The Origin and Early Evolution of Life: (Prebiotic) Systems Chemistry Perspective

Aristotle considered that “nature does not do anything endless” [...

Chemical-Induced Read-Through at Premature Termination Codons Determined by a Rapid Dual-Fluorescence System Based on S. cerevisiae

Nonsense mutations generate in-frame stop codons in mRNA leading to a premature arrest of translation. Functional consequences of premature termination codons (PTCs) include the synthesis of truncated proteins with loss of protein function causing severe inherited or acquired diseases. A therapeutic approach has been recently developed that is based on the use of chemical agents with the ability to suppress PTCs (read-through) restoring the synthesis of a functional full-length protein. Research interest for compounds able to induce read-through requires an efficient high throughput large scale screening system. We present a rapid, sensitive and quantitative method based on a dual-fluorescence reporter expressed in the yeast Saccharomyces cerevisiae to monitor and quantitate read-through at PTCs. We have shown that our novel system works equally well in detecting read-through at all three PTCs UGA, UAG and UAA