Oscillatory chemical reactions are functional components in a variety of biological contexts. In chemistry, the construction and identification of even rudimentary oscillators remain elusive and lack a general framework. Using parameter-rich kinetics-a methodology enabling the disentanglement of parametric dependencies from structural analysis-we investigate the stoichiometry of chemical oscillators. We introduce the concept of oscillatory cores: minimal subnetworks that guarantee the potential for oscillations in any reaction network containing them. These cores fall into two classes, depending on whether they involve positive or negative feedback. In particular, the latter class unveils a family of oscillators-yet to be synthesized-that requires a minimum number of reaction steps to exhibit oscillations, a phenomenon we refer to as the principle of length. We identify several mechanisms through which catalysis promotes oscillations: (I) furnishing instability (e.g. autocatalysis), (II) lifting dependencies, (III) lowering length thresholds. Notwithstanding this mechanistic ubiquity, we show that oscillators can also be realized without employing any catalysis. Our results highlight branches of chemistry where oscillators are likely to arise by chance, suggest new strategies for their design and point to novel classes of oscillators yet to be realized experimentally.
Frailty emerges as the intermediate stage preceding disability, but there is a gap in molecular signatures for early detection of subclinical cellular changes, which could help predict frailty onset or the effectiveness of interventions. In this randomized, controlled study, we assessed phenotypical and functional changes in frail individuals before and after a 6-month multidomain lifestyle intervention (nutritional supplement and supervised exercise) vs habitual care. We also analyzed whole-blood methylome, including five epigenetic clocks, a DNA methylation-based telomere length estimator, and the Rate of Epigenetic Aging (REA). Between October 2019 and July 2022, we recruited 47 frail, community-dwelling individuals in Spain. Mean age was 80.2 years (SD 3.1) in the control group (CG; n = 19) and 80.5 years (4.3) in the intervention group (IG; n = 28). Compared with the CG, a significant reduction in frailty, assessed by the SHARE-FI score, was observed in the IG (p < 0.0001). The IG also showed improved grip strength (p = 0.0053), gait speed (p = 0.0125), the Tinetti score (p = 0.0031), and Barthel Index (p = 0.0484). The intervention was also associated with statistically significant improvements in nutritional blood markers, indicators of biological aging, including reduced DNAm PhenoAge (p = 0.0253) and preserved telomere length (p = 0.0246). REA using DNAm PhenoAge indicated an acceleration of epigenetic aging in the CG (p = 0.0300). Other epigenetic clocks showed nonsignificant changes. Our findings suggest potential geroprotective effects of a multidomain intervention and indicate that DNAm PhenoAge and methylation-based telomere length may serve as complementary markers for assessing health span-related changes in frail older adults. Trial Registration: This trial was retrospectively registered: NCT06975540.
The problem of empirical estimation of mutation rates is fundamental to the understanding of viral evolution. The estimation of viral mutation rates is based on varied and often complex methods carried out through experiments essentially designed to count mutation frequencies. Mutation rates are defined as the probabilities of nucleotide substitutions, typically reported as a single number in units of mutation (substitution) per base (nucleotide) per replication cycle or per cell infection, depending on the replication mode of the virus. Even more, the uncertainty quantification of these estimates is so difficult that it is rare to find it reported in the literature. The values for the same virus reported in literature fall within a broad range, sometimes spanning two orders of magnitude. For instance, the mutation rates range from 10-8 to 10-6 mutations per base per cell infection for DNA viruses and from 10-6 to 10-4 mutations per base per cell infection for RNA viruses. The main issue here is that for the same viruses, there are several mutation rate estimates with different measuring units. In this paper, we propose an alternative perspective on the estimation of mutational rates, which avoids the use of serial passages. Our approach leverages the large amount of sequencing data produced by high-throughput sequencing technologies coupled to an experimental design that performs a single replication cycle from an initial clonal viral population. We propose to replace the single numeric mutation rate with a distribution of mutation rates (DMRs), together with a procedure to implement the estimation of this distribution from sequencing data, and show that it can be estimated from sequencing data. Even though the focus of this paper is the development of the approach centred on the DMR, it is straightforward to produce point and interval estimates of the mutation rates, including uncertainty quantification. In addition to the estimation of the DMR, we provide a theoretical characterization of it, as being well approximated by a log-normal distribution. Finally, we illustrate how the DMR can be used in non-trivial ways to study global properties of the genome. Namely, using methods of information theory, we show that there is a remarkable 'scaling invariance' related to the procedure of localization of the DMR from the whole genome to its genomic subunits.
Streptococcus pneumoniae is a leading cause of lower respiratory tract (LRT) infections and invasive pneumococcal diseases (IPD). Conjugate vaccines are effective against IPD and nasal colonization but offer coverage limited to serotypes included in the formulations. Pneumococcal surface protein A (PspA) stands out as a promising vaccine antigen. We had previously shown that recombinant adenylate cyclase toxoid from Bordetella pertussis (CyaA) carrying PspA fragments induces humoral responses and protection against pneumococcal infection in mice. Here, we present an optimized construct combining fragments derived from four PspA variants (CyaA-A2-A4/A1-A3). Immunization of mice with CyaA-A2-A4/A1-A3 conferred protection against IPD and promoted a rapid control of LRT infection. Antibody reactivity and protection were observed across strains expressing distinct PspAs and capsular serotypes. Importantly, CyaA-A2-A4/A1-A3 protected mice against serotype 3 isolates from clonal complex 180, a major clone causing disease worldwide. CyaA-A2-A4/A1-A3 may be proposed as a complementary vaccine to induce broad protection against pneumococcal infections.
The presence of surfactants in natural waters has become a growing environmental concern, as these substances, widely used in detergents, cleaning products, cosmetics, and industrial processes, can cause serious impacts on aquatic ecosystems, including deleterious effects on biota, depletion of dissolved oxygen, and eutrophication. This study presents a battery of ecotoxicological assays with different aquatic organisms to evaluate the acute, chronic, and sublethal toxic effects of anionic surfactants Linear Alkylbenzene Sulfonate (LAS) and Sodium Dodecyl Sulfate (SDS). The assays were performed with Vibrio fischeri bacteria, Daphnia similis crustaceans, Hyalella azteca amphipods, and Biomphalaria glabrata snails. Regarding LAS acute exposure, H. azteca was the most sensitive organism, followed by D. similis, B. glabrata, and V. fischeri, with E(L)C50 between 5.04 and 28.47 mg/L. Among the organisms exposed to SDS, the most sensitive were V. fischeri bacteria, followed by D. similis, H. azteca, and B. glabrata, with E(L)C50 values between 0.62 and 36.87 mg/L. Chronic effects on the reproduction of D. similis exposed to both surfactants were also observed, as well as teratogenic and lethal effects on B. glabrata embryos. The data obtained herein demonstrated the importance of evaluating the toxicity of surfactants to aquatic ecosystems, as these stressors caused different adverse effects in the exposed species.
