Phase Transition in Sexual Reproduction and Biological Evolution

Using Monte Carlo model of biological evolution we have discovered that populations can switch between two different strategies of their genomes' evolution; Darwinian purifying selection and complementing the haplotypes. The first one is exploited in the large panmictic populations while the second one in the small highly inbred populations. The choice depends on the crossover frequency. There is a power law relation between the critical value of crossover frequency and the size of panmictic population. Under the constant inbreeding this critical value of crossover does not depend on the population size and has a character of phase transition. Close to this value sympatric speciation is observed.Comment: 13 pages, 8 figure

Bodybuilders' accounts of synthol use: The construction of lay expertise online.

Synthol is an injectable oil used by bodybuilders to make muscles appear bigger. Widely available on the Internet, it is reported to carry a wide range of health risks and side effects such as localised skin problems, nerve damage and oil-filled cysts, as well as muscle damage and the development of scar tissue. Given the tension between health risk and quick muscle enlargement, how lay users explain and justify their synthol intake becomes an important question. Drawing on discourse analysis, we focus on how lay expertise is worked up by users in the absence of available specialist knowledge by invoking medical and pharmaceutical discourses as legitimation, providing novices with support, gaining trust through positive personal narratives and thus gaining credibility as experts. Results have clear implications for health promotion interventions with bodybuilders

Phase transition in the genome evolution favours non-random distribution of genes on chromosomes

We have used the Monte Carlo based computer models to show that selection pressure could affect the distribution of recombination hotspots along the chromosome. Close to critical crossover rate, where genomes may switch between the Darwinian purifying selection or complementation of haplotypes, the distribution of recombination events and the force of selection exerted on genes affect the structure of chromosomes. The order of expression of gene s and their location on chromosome may decide about the extinction or survival of competing populations.Comment: 13 pages, 7 figures, publicatio

A designer hyper interleukin 11 (H11) is a biologically active cytokine

<p>Abstract</p> <p>Background</p> <p>Interleukin 11 (IL-11) is a pleiotropic cytokine with anti-apoptotic, anti-inflammatory and hematopoietic potential. The IL-11 activity is determined by the expression of the IL-11R receptor alpha (IL-11Rα) and the signal transducing subunit β (gp130) on the cell membrane. A recombinant soluble form of the IL-11Rα (sIL-11Rα) in combination with IL-11 acts as an agonist on cells expressing the gp130 molecule. We constructed a designer cytokine Hyper IL-11 (H11), which is exclusively composed of naturally existing components. It contains the full length sIL-11Rα connected with the mature IL-11 protein using their natural sequences only. Such a construct has two major advantages: (i) its components are as close as possible to the natural forms of both proteins and (ii) it lacks an artificial linker what should avoid induction of antibody production.</p> <p>Results</p> <p>The H11 construct was generated, the protein was produced in a baculovirus expression system and was then purified by using ion exchange chromatography. The H11 protein displayed activity in three independent bioassays, (i) it induced acute phase proteins production in HepG2 cells expressing IL-11, IL-11Rα and gp130, (ii) it stimulated the proliferation of B9 cells (cells expressing IL-11Rα and gp130) and (iii) proliferation of Baf/3-gp130 cells (cells not expressing IL-11 and IL-11Rα but gp130). Moreover, the preliminary data indicated that H11 was functionally distinct from Hyper-IL-6, a molecule which utilizes the same homodimer of signal transducing receptor (gp130).</p> <p>Conclusions</p> <p>The biologically active H11 may be potentially useful for treatment of thrombocytopenia, infertility, multiple sclerosis, cardiovascular diseases or inflammatory disorders.</p

Modelling survival and allele complementation in the evolution of genomes with polymorphic loci

We have simulated the evolution of sexually reproducing populations composed of individuals represented by diploid genomes. A series of eight bits formed an allele occupying one of 128 loci of one haploid genome (chromosome). The environment required a specific activity of each locus, this being the sum of the activities of both alleles located at the corresponding loci on two chromosomes. This activity is represented by the number of bits set to zero. In a constant environment the best fitted individuals were homozygous with alleles’ activities corresponding to half of the environment requirement for a locus (in diploid genome two alleles at corresponding loci produced a proper activity). Changing the environment under a relatively low recombination rate promotes generation of more polymorphic alleles. In the heterozygous loci, alleles of different activities complement each other fulfilling the environment requirements. Nevertheless, the genetic pool of populations evolves in the direction of a very restricted number of complementing haplotypes and a fast changing environment kills the population. If simulations start with all loci heterozygous, they stay heterozygous for a long time

Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial

Background Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics. Methods Patients aged ≥ 12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness ( ≤ 4 mm vs \u3e 4 mm), presence of ulceration (yes vs no), mitotic rate ( \u3c 5 per mm 2 (median) vs ≥ 5 per mm 2), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present). Results Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0-39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤ 4 mm and 0.69 (0.50 to 0.96) for \u3e 4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate \u3c 5 per mm 2 and 0.57 (0.40 to 0.80) for ≥ 5 per mm 2; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS. Conclusions In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma. Trial registration number ClinicalTrials.gov, NCT03553836

Limits of Calcium Clearance by Plasma Membrane Calcium ATPase in Olfactory Cilia

BACKGROUND: In any fine sensory organelle, a small influx of Ca(2+) can quickly elevate cytoplasmic Ca(2+). Mechanisms must exist to clear the ciliary Ca(2+) before it reaches toxic levels. One such organelle has been well studied: the vertebrate olfactory cilium. Recent studies have suggested that clearance from the olfactory cilium is mediated in part by plasma membrane Ca(2+)-ATPase (PMCA). PRINCIPAL FINDINGS: In the present study, electrophysiological assays were devised to monitor cytoplasmic free Ca(2+) in single frog olfactory cilia. Ca(2+) was allowed to enter isolated cilia, either through the detached end or through membrane channels. Intraciliary Ca(2+) was monitored via the activity of ciliary Ca(2+)-gated Cl(-) channels, which are sensitive to free Ca(2+) from about 2 to 10 microM. No significant effect of MgATP on intraciliary free Ca(2+) could be found. Carboxyeosin, which has been used to inhibit PMCA, was found to substantially increase a ciliary transduction current activated by cyclic AMP. This increase was ATP-independent. CONCLUSIONS: Alternative explanations are suggested for two previous experiments taken to support a role for PMCA in ciliary Ca(2+) clearance. It is concluded that PMCA in the cilium plays a very limited role in clearing the micromolar levels of intraciliary Ca(2+) produced during the odor response

Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Final analysis of distant metastasis-free survival in the phase III KEYNOTE-716 study

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Pembrolizumab adjuvant therapy was shown to significantly improve recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB or IIC melanoma in earlier analyses of the randomized, double-blind, phase III KEYNOTE-716 study (ClinicalTrials.gov identifier: NCT03553836). We report results of the protocol-specified final analysis of DMFS for KEYNOTE-716. Overall, 976 patients were randomly allocated to pembrolizumab (n = 487) or placebo (n = 489). As of January 4, 2023, median follow-up was 39.4 months (range, 26.0-51.4 months). The median DMFS was not reached in either treatment group, and the estimated 36-month DMFS was 84.4% for pembrolizumab and 74.7% for placebo (hazard ratio [HR], 0.59 [95% CI, 0.44 to 0.79]). The median RFS was not reached in either treatment group, and the estimated 36-month RFS was 76.2% for pembrolizumab and 63.4% for placebo (HR, 0.62 [95% CI, 0.49 to 0.79]). DMFS and RFS results were consistent across most prespecified subgroups, including stage IIB and stage IIC melanoma. The safety profile of pembrolizumab was manageable and consistent with previous reports. These results continue to support the use of pembrolizumab adjuvant therapy in patients with resected stage IIB or IIC melanoma

Reasoning from connectives and relations between entities

This article reports investigations of inferences that depend both on connectives between clauses, such as or else, and on relations between entities, such as in the same place as. Participants made more valid inferences from biconditionals—for instance, Ann is taller than Beth if and only if Beth is taller than Cath—than from exclusive disjunctions (Exp. 1). They made more valid transitive inferences from a biconditional when a categorical premise affirmed rather than denied one of its clauses, but they made more valid transitive inferences from an exclusive disjunction when a categorical premise denied rather than affirmed one of its clauses (Exp. 2). From exclusive disjunctions, such as Either Ann is not in the same place as Beth or else Beth is not in the same place as Cath, individuals tended to infer that all three individuals could be in different places, whereas in fact this was impossible (Exps. 3a and 3b). The theory of mental models predicts all of these results