The function of the organism hinges on the performance of its information-processing networks, which convey information via molecular recognition. Many paths within these networks utilize molecular codebooks, such as the genetic code, to translate information written in one class of molecules into another molecular "language" . The present paper examines the emergence and evolution of molecular codes in terms of rate-distortion theory and reviews recent results of this approach. We discuss how the biological problem of maximizing the fitness of an organism by optimizing its molecular coding machinery is equivalent to the communication engineering problem of designing an optimal information channel. The fitness of a molecular code takes into account the interplay between the quality of the channel and the cost of resources which the organism needs to invest in its construction and maintenance. We analyze the dynamics of a population of organisms that compete according to the fitness of their codes. The model suggests a generic mechanism for the emergence of molecular codes as a phase transition in an information channel. This mechanism is put into biological context and demonstrated
Local drug delivery has received much recognition in recent years, yet it is still unpredictable how drug efficacy depends on physicochemical properties and delivery kinetics. The purpose of the current study is to provide a useful mathematical model for drug release from a drug delivery device and consecutive drug transport in biological tissue, thereby aiding the development of new therapeutic drug by a systemic approach. In order to study the complete process, a two-layer spatio-temporal model depicting drug transport between the coupled media is presented. Drug release is described by considering solubilisation dynamics of drug particle, diffusion of the solubilised drug through porous matrix and also some other processes like reversible dissociation / recrystallization, drug particle-receptor binding and internalization phenomena. The model has led to a system of partial differential equations describing the important properties of drug kinetics. This model contributes towards the perception of the roles played by diffusion, mass-transfer, particle binding and internalization parameters.
Despite all the advances achieved in the field of tumor-biology research, in most cases conventional therapies including chemotherapy are still the leading choices. The main disadvantage of these treatments, in addition to the low solubility of many antitumor drugs, is their lack of specificity, which explains the frequent occurrence of serious side effects due to nonspecific drug uptake by healthy cells. Progress in nanotechnology and its application in medicine have provided new opportunities and different smart systems. Such systems can improve the intracellular delivery of the drugs due to their multifunctionality and targeting potential. The purpose of this manuscript is to review and analyze the recent progress made in nanotherapy applied to cancer treatment. First, we provide a global overview of cancer and different smart nanoparticles currently used in oncology. Then, we analyze in detail the development of drug-delivery strategies in cancer therapy, focusing mainly on the intravenously administered smart nanoparticles with protein corona to avoid immune-system clearance. Finally, we discuss the challenges, clinical trials, and future directions of the nanoparticle-based t
What makes living things special is how they manage matter, energy, and entropy. A general theory of organismal metabolism should therefore be quantified in these three currencies while capturing the unique way they flow between individuals and their environments. We argue that such a theory has quietly arrived -- 'Dynamic Energy Budget' (DEB) theory -- which conceptualises organisms as a series of macrochemical reactions that use energy to transform food into structured biomass and bioproducts while producing entropy. We show that such conceptualisation is deeply rooted in thermodynamic principles and that, with the help of a small set of biological assumptions, it underpins the emergence of fundamental ecophysiological phenomena, most notably the three-quarter power scaling of metabolism. Building on the subcellular nature of the theory, we unveil the eco-evolutionary relevance of coarse-graining biomass into qualitatively distinct, stoichiometricially fixed pools with implicitly regulated dynamics based on surface area-volume relations. We also show how generalised enzymes called 'synthesising units' and an information-based state variable called 'maturity' capture transitions b
Motivation: Analysis of relationships of drug structure to biological response is key to understanding off-target and unexpected drug effects, and for developing hypotheses on how to tailor drug thera-pies. New methods are required for integrated analyses of a large number of chemical features of drugs against the corresponding genome-wide responses of multiple cell models. Results: In this paper, we present the first comprehensive multi-set analysis on how the chemical structure of drugs impacts on ge-nome-wide gene expression across several cancer cell lines (CMap database). The task is formulated as searching for drug response components across multiple cancers to reveal shared effects of drugs and the chemical features that may be responsible. The com-ponents can be computed with an extension of a very recent ap-proach called Group Factor Analysis (GFA). We identify 11 compo-nents that link the structural descriptors of drugs with specific gene expression responses observed in the three cell lines, and identify structural groups that may be responsible for the responses. Our method quantitatively outperforms the limited earlier studies on CMap and identifies both the previously
Detailed and systematic understanding of the biological effects of millions of available compounds on living cells is a significant challenge. As most compounds impact multiple targets and pathways, traditional methods for analyzing structure-function relationships are not comprehensive enough. Therefore more advanced integrative models are needed for predicting biological effects elicited by specific chemical features. As a step towards creating such computational links we developed a data-driven chemical systems biology approach to comprehensively study the relationship of 76 structural 3D-descriptors (VolSurf, chemical space) of 1159 drugs with the gene expression responses (biological space) they elicited in three cancer cell lines. The analysis covering 11350 genes was based on data from the Connectivity Map. We decomposed these biological response profiles into components, each linked to a characteristic chemical descriptor profile. The integrated quantitative analysis of the chemical and biological spaces was more informative about protein-target based drug similarity than either dataset separately. We identified ten major components that link distinct VolSurf features acros
Aims. Resistance to targeted therapies remains a major challenge in EGFR-mutant non-small cell lung cancer (NSCLC). Here, we describe a novel metabolic adaptation in osimertinib-resistant cells characterized by elevated acetate levels and activation of an unconventional pyruvate-acetaldehyde-acetate (PAA) shunt. Methods. Integrated transcriptomic, exometabolomic, and functional analyses reveal suppression of canonical metabolic pathways and upregulation of ALDH2 and ALDH7A1, that mediate the NADP+-dependent oxidation of acetaldehyde to acetate, generating NADPH. Results. This shift generates reducing power essential for biosynthesis and redox balance under conditions of oxidative pentose phosphate inhibition. These metabolic changes promote endurance in resistant cells and rewire the interplay between glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle, offering a de novo bypass for anaplerosis and bioenergetics. Systematic metabolite profiling revealed distinct transcriptomic and metabolic signatures distinguishing resistant from drug sensitive parental cells. Conclusions. Together, these findings depict a unique, resistance-driven adaptive metabolic shift
High-throughput screening (HTS) is useful for evaluating chemicals for potential human health risks. However, given the extraordinarily large number of genes, assay endpoints, and chemicals of interest, available data are sparse, with dose-response curves missing for the vast majority of chemical-gene pairs. Although gene ontologies characterize similarity among genes with respect to known cellular functions and biological pathways, the sensitivity of various pathways to environmental contaminants remains unclear. We propose a novel Dose-Activity Response Tracking (DART) approach to predict the biological activity of chemicals across genes using information on chemical structural properties and gene ontologies within a Bayesian factor model. Designed to provide toxicologists with a flexible tool applicable across diverse HTS assay platforms, DART reveals the latent processes driving dose-response behavior and predicts new activity profiles for chemical-gene pairs lacking experimental data. We demonstrate the performance of DART through simulation studies and an application to a vast new multi-experiment data set consisting of dose-response observations generated by the exposure of
"How to evaluate the de novo designs proposed by a generative model?" Despite the transformative potential of generative deep learning in drug discovery, this seemingly simple question has no clear answer. The absence of standardized guidelines challenges both the benchmarking of generative approaches and the selection of molecules for prospective studies. In this work, we take a fresh - critical and constructive - perspective on de novo design evaluation. By training chemical language models, we analyze approximately 1 billion molecule designs and discover principles consistent across different neural networks and datasets. We uncover a key confounder: the size of the generated molecular library significantly impacts evaluation outcomes, often leading to misleading model comparisons. We find increasing the number of designs as a remedy and propose new and compute-efficient metrics to compute at large-scale. We also identify critical pitfalls in commonly used metrics - such as uniqueness and distributional similarity - that can distort assessments of generative performance. To address these issues, we propose new and refined strategies for reliable model comparison and design evalu
We investigate phase space transport in a two-dimensional stretched caldera potential using the Origin-Fate Map (OFM) framework, complemented by Lagrangian Descriptor (LD) analysis. The caldera potential, a model for reaction dynamics with multiple exit channels, is adjusted by a stretching factor lambda that controls the directional bias of the four-saddle landscape. Several OFMs are constructed for two Poincare surfaces of section using forwards and backwards symplectic integration to assign each initial condition a channel of origin and fate. Our results reproduce the highly symmetric lambda = 1.0 patterns reported in Hillebrand et al. (Phys. Rev. E 108, 024211, 2023), and reveal, for smaller lambda, pronounced channel imbalance, figure-eight transport loops, and complex mixed-channel chaotic regions. Long-time integrations show a reduction of trapped regions with boundaries that exhibit self-similarity under deep zoom, revealing fractal-like structures. High-resolution OFMs and LD gradient maps uncover lobe dynamics and manifold structures that govern transport, showing near-perfect alignment between LD ridges and OFM boundaries.
Longer timelines and lower success rates of drug candidates limit the productivity of clinical trials in the pharmaceutical industry. Promising de novo drug design techniques help solve this by exploring a broader chemical space, efficiently generating new molecules, and providing improved therapies. However, optimizing for molecular characteristics found in approved oral drugs remains a challenge, limiting de novo usage. In this work, we propose NovoMol, a novel de novo method using recurrent neural networks to mass-generate drug molecules with high oral bioavailability, increasing clinical trial time efficiency. Molecules were optimized for desirable traits and ranked using the quantitative estimate of drug-likeness (QED). Generated molecules meeting QED's oral bioavailability threshold were used to retrain the neural network, and, after five training cycles, 76% of generated molecules passed this strict threshold and 96% passed the traditionally used Lipinski's Rule of Five. The trained model was then used to generate specific drug candidates for the cancer-related PDGFRα receptor and 44% of generated candidates had better binding affinity than the current state-of-the-art drug,
A distinct feature of pancreatic ductal adenocarcinoma (PDAC) is a prominent tumor microenvironment (TME) with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. The dynamic crosstalk between cancer cells and the dense stromal compartment leads to spatially and temporally heterogeneous metabolic alterations, such as acidic pH that contributes to drug resistance in PDAC. Thus, monitoring the extracellular pH metabolic fluctuations within the TME is crucial to predict and to quantify anticancer drug efficacy. Here, a simple and reliable alginate-based 3D PDAC model embedding ratiometric optical pH sensors and cocultures of tumor (AsPC-1) and stromal cells for simultaneously monitoring metabolic pH variations and quantify drug response is presented. By means of time-lapse confocal laser scanning microscopy (CLSM) coupled with a fully automated computational analysis, the extracellular pH metabolic variations are monitored and quantified over time during drug testing with gemcitabine, folfirinox, and paclitaxel, commonly used in PDAC therapy. In particular, the extracellular acidification is more pronounced after drugs trea
We present the results of processing the effects of the powerful Gamma Ray Burst GRB221009A captured by the charged particle detectors (electrostatic analyzers and solid-state detectors) onboard spacecraft at different points in the heliosphere on October 9, 2022. To follow the GRB221009A propagation through the heliosphere we used the electron and proton flux measurements from solar missions Solar Orbiter and STEREO-A; Earth magnetosphere and the solar wind missions THEMIS and Wind; meteorological satellites POES15, POES19, MetOp3; and MAVEN - a NASA mission orbiting Mars. GRB221009A had a structure of four bursts: less intense Pulse 1 - the triggering impulse - was detected by gamma-ray observatories at 131659 UT (near the Earth); the most intense Pulses 2 and 3 were detected on board all the spacecraft from the list, and Pulse 4 detected in more than 500 s after Pulse 1. Due to their different scientific objectives, the spacecraft, which data was used in this study, were separated by more than 1 AU (Solar Orbiter and MAVEN). This enabled tracking GRB221009A as it was propagating across the heliosphere. STEREO-A was the first to register Pulse 2 and 3 of the GRB, almost 100 secon
Biological systems possess negative entropy. In them, one form of order produces another, more organized form of order. We propose a formal scheme to calculate robustness of an entire biological system by quantifying the negative entropy present in it. Our Methodology is based upon a computational implementation of two-person non-cooperative finite zero-sum game between positive (physico-chemical) and negative (biological) entropy, present in the system(TCA cycle, for this work). Biochemical analogue of Nash equilibrium, proposed here, could measure the robustness in TCA cycle in exact numeric terms, whereas the mixed strategy game between these entropies could quantitate the progression of stages of biological adaptation. Synchronization profile amongst macromolecular concentrations (even under environmental perturbations) is found to account for negative entropy and biological robustness. Emergence of synchronization profile was investigated with dynamically varying metabolite concentrations. Obtained results were verified with that from the deterministic simulation methods. Categorical plans to apply this algorithm in Cancer studies and anti-viral therapies are proposed alongsid
We extend a previously theory for the interspecific allometric scaling developed in a $d+1$-dimensional space of metabolic states. The time, which is characteristic of all biological processes, is included as an extra dimension to $d$ biological lengths. The different metabolic rates, such as basal (BMR) and maximum (MMR), are described by supposing that the biological lengths and time are related by different transport processes of energy and mass. We consider that the metabolic rates of animals are controlled by three main transport processes: convection, diffusion and anomalous diffusion. Different transport mechanisms are related to different metabolic states, with its own values for allometric exponents. In $d=3$, we obtain that the exponent $b$ of BMR is $b=0.71$, and that the aerobic sustained MMR upper value of the exponent is $b=0.86$ (best empirical values for mammals: $b=0.69(2)$ and $b=0.87(3)$). The 3/4-law appears as an upper limit of BMR. The MMR scaling in different conditions, other exponents related to BMR and MMR, and the metabolism of unicellular organisms are also discussed.
Despite a strong desire to quit, individuals with long-term substance use disorder (SUD) often struggle to resist drug use, even when aware of its harmful consequences. This disconnect between knowledge and compulsive behavior reflects a fundamental cognitive-behavioral conflict in addiction. Neurobiologically, differential cue-induced activity within striatal subregions, along with dopamine-mediated connectivity from the ventral to the dorsal striatum, contributes to compulsive drug-seeking. However, the functional mechanism linking these findings to behavioral conflict remains unclear. Another hallmark of addiction is temporal discounting: individuals with drug dependence exhibit steeper discount rates than non-users. Assuming the ventral-dorsal striatal organization reflects a gradient from cognitive to motor representations, addiction can be modeled within a hierarchical reinforcement learning (HRL) framework. However, integrating discounting into biologically grounded HRL remains an open challenge. In this work, we build on a model showing how action choices reinforced with drug rewards become insensitive to the negative consequences that follow. We address the integration of
Phosphorus (P) is considered to be one of the key elements for life, making it an important element to look for in the abundance analysis of spectra of stellar systems. Yet, there exists only a handful of spectroscopic studies to estimate the P abundances and investigate its trend across a range of metallicities. We have observed full HK band spectra at a spectral resolving power of R=45,000 with IGRINS instrument. Abundances are determined using SME in combination with 1D MARCS stellar atmosphere models. The investigated sample of stars have reliable stellar parameters estimated using optical FIES spectra (GILD; Jönsson et al. in prep.). In order to determine the P abundances from the 16482.92 Angstrom P line, we take special care of the CO($ν=7-4$) blend. We determine the C, N, O abundances from atomic carbon and a range of non-blended molecular lines (CO, CN, OH) which are aplenty in the H band region of K giant stars, assuring an appropriate modelling of the blending CO($ν=7-4$) line. We present [P/Fe] vs [Fe/H] trend for 38 K giant stars in the metallicity range of -1.2 dex $<$ [Fe/H] $<$ 0.4 dex. We find that our trend matches well with the compiled literature sample of
Recently, bacterial nanocellulose (BNC), a biological material produced by non-pathogenic bacteria that possesses excellent material properties for various medical applications, has received increased interest as a carrier system for drug delivery. However, the vast majority of existing studies on drug release from BNC are feasibility studies with modeling and design aspects remaining largely unexplored. To narrow this research gap, this paper proposes a novel model for the drug release from BNC. Specifically, the drug delivery system considered in this paper consists of a BNC fleece coated with a polymer. The polymer coating is used as an additional diffusion barrier, enabling the controlled release of an active pharmaceutical ingredient. The proposed physics-based model reflects the geometry of the BNC and incorporates the impact of the polymer coating on the drug release. Hence, it can be useful for designing BNC-based drug delivery systems in the future. The accuracy of the model is validated with experimental data obtained in wet lab experiments.
Despite the great popularity of virtual screening of existing compound libraries, the search for new potential drug candidates also takes advantage of generative protocols, where new compound suggestions are enumerated using various algorithms. To increase the activity potency of generative approaches, they have recently been coupled with molecular docking, a leading methodology of structure-based drug design. In this review, we summarize progress since docking-based generative models emerged. We propose a new taxonomy for these methods and discuss their importance for the field of computer-aided drug design. In addition, we discuss the most promising directions for further development of generative protocols coupled with docking.
Spoken medical dialogue systems are increasingly attracting interest to enhance access to healthcare services and improve quality and traceability of patient care. In this paper, we focus on medical drug prescriptions acquired on smartphones through spoken dialogue. Such systems would facilitate the traceability of care and would free clinicians' time. However, there is a lack of speech corpora to develop such systems since most of the related corpora are in text form and in English. To facilitate the research and development of spoken medical dialogue systems, we present, to the best of our knowledge, the first spoken medical drug prescriptions corpus, named PxSLU. It contains 4 hours of transcribed and annotated dialogues of drug prescriptions in French acquired through an experiment with 55 participants experts and non-experts in prescriptions. We also present some experiments that demonstrate the interest of this corpus for the evaluation and development of medical dialogue systems.