Minimal Morphoelastic Models of Solid Tumour Spheroids: A Tutorial

Tumour spheroids have been the focus of a variety of mathematical models, ranging from Greenspan's classical study of the 1970 s through to contemporary agent-based models. Of the many factors that regulate spheroid growth, mechanical effects are perhaps some of the least studied, both theoretically and experimentally, though experimental enquiry has established their significance to tumour growth dynamics. In this tutorial, we formulate a hierarchy of mathematical models of increasing complexity to explore the role of mechanics in spheroid growth, all the while seeking to retain desirable simplicity and analytical tractability. Beginning with the theory of morphoelasticity, which combines solid mechanics and growth, we successively refine our assumptions to develop a somewhat minimal model of mechanically regulated spheroid growth that is free from many unphysical and undesirable behaviours. In doing so, we will see how iterating upon simple models can provide rigorous guarantees of emergent behaviour, which are often precluded by existing, more complex modelling approaches. Perhaps surprisingly, we also demonstrate that the final model considered in this tutorial agrees favourably with classical experimental results, highlighting the potential for simple models to provide mechanistic insight whilst also serving as mathematical examples

Severe Inflammation Following Vaccination Against Streptococcus pneumoniae in Patients With Cryopyrin-Associated Periodic Syndromes

OBJECTIVE: Pneumococcal vaccination is recommended for patients receiving immunosuppressive drugs. We describe unusually severe adverse reactions to pneumococcal vaccination in each of 7 consecutive patients with cryopyrin-associated periodic syndromes (CAPS). METHODS: Seven consecutive patients with CAPS were vaccinated with pneumococcal polysaccharide or conjugate vaccines. Clinical information was collected retrospectively. RESULTS: Within a few hours after the vaccination, all 7 patients developed severe local reactions at the injection site. Two patients had to be hospitalized for systemic reactions including fever. All symptoms resolved in a period of 3–17 days. CONCLUSION: Our findings indicate that pneumococcal vaccines can trigger a severe local and systemic inflammatory reaction in patients with CAPS and possibly patients with other autoinflammatory diseases. Careful consideration is warranted when implementing current European League Against Rheumatism immunization guidelines in this patient population

Malignant hypertension and acute aortic dissection associated with caffeine-based ephedra-free dietary supplements: a case report

The use of weight loss dietary supplements is prevalent in the United States, and over the past decade, there has been tremendous growth of the use of these products. It is well documented that ephedra-based products are associated with various cardiovascular adverse effects. With new restrictions placed on such products, companies are now manufacturing caffeine-based ephedra-free herbal supplements. We present the case of 36-year old, previously healthy female who developed malignant hypertension and aortic dissection while taking various caffeine-based dietary supplements. Given the lack of research studies in regards to their safety and efficacy, judicious care should be taken with the use of dietary supplements, including those designated as ephedra-free

The psychological foundations of reputation-based cooperation

Humans care about having a positive reputation, which may prompt them to help in scenarios where the return benefits are not obvious. Various game-theoretical models support the hypothesis that concern for reputation may stabilize cooperation beyond kin, pairs or small groups. However, such models are not explicit about the underlying psychological mechanisms that support reputation-based cooperation. These models therefore cannot account for the apparent rarity of reputation-based cooperation in other species. Here, we identify the cognitive mechanisms that may support reputation-based cooperation in the absence of language. We argue that a large working memory enhances the ability to delay gratification, to understand others' mental states (which allows for perspective-taking and attribution of intentions) and to create and follow norms, which are key building blocks for increasingly complex reputation-based cooperation. We review the existing evidence for the appearance of these processes during human ontogeny as well as their presence in non-human apes and other vertebrates. Based on this review, we predict that most non-human species are cognitively constrained to show only simple forms of reputation-based cooperation. This article is part of the theme issue ‘The language of cooperation: reputation and honest signalling’

Human C4orf14 interacts with the mitochondrial nucleoid and is involved in the biogenesis of the small mitochondrial ribosomal subunit.

The bacterial homologue of C4orf14, YqeH, has been linked to assembly of the small ribosomal subunit. Here, recombinant C4orf14 isolated from human cells, co-purified with the small, 28S subunit of the mitochondrial ribosome and the endogenous protein co-fractionated with the 28S subunit in sucrose gradients. Gene silencing of C4orf14 specifically affected components of the small subunit, leading to decreased protein synthesis in the organelle. The GTPase of C4orf14 was critical to its interaction with the 28S subunit, as was GTP. Therefore, we propose that C4orf14, with bound GTP, binds to components of the 28S subunit facilitating its assembly, and GTP hydrolysis acts as the release mechanism. C4orf14 was also found to be associated with human mitochondrial nucleoids, and C4orf14 gene silencing caused mitochondrial DNA depletion. In vitro C4orf14 is capable of binding to DNA. The association of C4orf14 with mitochondrial translation factors and the mitochondrial nucleoid suggests that the 28S subunit is assembled at the mitochondrial nucleoid, enabling the direct transfer of messenger RNA from the nucleoid to the ribosome in the organelle.Medical Research Council (MRC); Biotechnology and Biological Sciences Research Council (BBSRC); European Union; Academy of Finland (to H.M.C.). Funding for open access charge: MRC

Long-term safety and effectiveness of canakinumab therapy in patients with cryopyrin-associated periodic syndrome: results from the β-Confident Registry.

OBJECTIVE: To report the long-term safety and effectiveness of canakinumab, a fully human anti-interleukin 1β monoclonal antibody, in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID), in a real-world setting. METHODS: From December 2009 to December 2015, the β-Confident Registry prospectively enrolled patients with CAPS and non-CAPS conditions who received canakinumab per routine care and were prospectively followed for up to 6 years. The registry protocol did not mandate specific visits or procedures; however, all observed adverse events (AEs) and serious adverse events (SAEs) had to be recorded. Canakinumab effectiveness was evaluated by Physician's Global Assessment (PGA). RESULTS: Of 288 patients enrolled, 3 were excluded due to missing informed consent. Among the remaining 285 patients, 243 (85.3%) were patients with CAPS and 42 (14.7%) had atypical CAPS (6.3%) or other conditions (8.4%). The median age was 26.6 years. Based on PGA, 58 of 123 (47.2%) patients with CAPS had no disease activity at 48 months, and 65 of 123 (52.8%) experienced mild/moderate disease activity at 48 months. Among CAPS phenotypes, AE incidence rates per 100 patient-years were lowest for FCAS (73.1; 95% CI 60.3 to 87.8) compared with those with MWS (105.0; 95% CI 97.2 to 113.2) or NOMID (104.6; 95% CI 86.6 to 125.2). One hundred twenty-eight SAEs were reported in 68 patients with CAPS (incidence rate/100 patient-years, 14.0; 95% CI 11.6 to 16.6). One death (metastatic rectal adenocarcinoma in a patient with MWS) was reported. CONCLUSIONS: The response to canakinumab was sustained for up to 6 years. Canakinumab demonstrated a favourable safety profile over long-term treatment in patients with CAPS. TRIAL REGISTRATION NUMBER: NCT01213641

Adaptation of Saccharomyces cerevisiae Cells to High Ethanol Concentration and Changes in Fatty Acid Composition of Membrane and Cell Size

BACKGROUND: Microorganisms can adapt to perturbations of the surrounding environment to grow. To analyze the adaptation process of the yeast Saccharomyces cerevisiae to a high ethanol concentration, repetitive cultivation was performed with a stepwise increase in the ethanol concentration in the culture medium. METHODOLOGY/PRINCIPAL FINDINGS: First, a laboratory strain of S. cerevisiae was cultivated in medium containing a low ethanol concentration, followed by repetitive cultivations. Then, the strain repeatedly cultivated in the low ethanol concentration was transferred to medium containing a high ethanol concentration and cultivated repeatedly in the same high-ethanol-concentration medium. When subjected to a stepwise increase in ethanol concentration with the repetitive cultivations, the yeast cells adapted to the high ethanol concentration; the specific growth rate of the adapted yeast strain did not decrease during repetitive cultivation in the medium containing the same ethanol concentration, while that of the non-adapted strain decreased during repetitive cultivation. A comparison of the fatty acid composition of the cell membrane showed that the contents in oleic acid (C(18:1)) in ethanol-adapted and non-adapted strains were similar, but the content of palmitic acid (C(16:0)) in the ethanol-adapted strains was lower than that in the non-adapted strain in media containing ethanol. Moreover, microscopic observation showed that the mother cells of the adapted yeast were significantly larger than those of the non-adapted strain. CONCLUSIONS: Our results suggest that activity of cell growth defined by specific growth rate of the yeast cells adapted to stepwise increase in ethanol concentration did not decrease during repetitive cultivation in high-ethanol-concentration medium. Moreover, fatty acid content of cell membrane and the size of ethanol-adapted yeast cells were changed during adaptation process. Those might be the typical phenotypes of yeast cells adapted to high ethanol concentration. In addition, the difference in sizes of the mother cell between the non-adapted and ethanol strains suggests that the cell size, cell cycle and adaptation to ethanol are thought to be closely correlated

Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis.

Mitochondrial ribosomes and translation factors co-purify with mitochondrial nucleoids of human cells, based on affinity protein purification of tagged mitochondrial DNA binding proteins. Among the most frequently identified proteins were ATAD3 and prohibitin, which have been identified previously as nucleoid components, using a variety of methods. Both proteins are demonstrated to be required for mitochondrial protein synthesis in human cultured cells, and the major binding partner of ATAD3 is the mitochondrial ribosome. Altered ATAD3 expression also perturbs mtDNA maintenance and replication. These findings suggest an intimate association between nucleoids and the machinery of protein synthesis in mitochondria. ATAD3 and prohibitin are tightly associated with the mitochondrial membranes and so we propose that they support nucleic acid complexes at the inner membrane of the mitochondrion.Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC); Intramural program of the National Institutes of Health, National Heart, Lung and Blood Institute (to K.N.); Academy of Finland (to H.M.C.). Funding for open access charge: MRC