Character space restrictions and boundary conditions in the evolution of quantitative multistate characters.

The effects of restrictions of available character space on the mean morphological distance between living members of evolutionary phylads are examined by Monte Carlo simulation. The approach involves specifying the degree to which ancestor-descendant species may differ and limiting the range of attainable character states within a phylad. Morphological evolution is modeled as a Markovian process involving quantitative multistate characters. States for a given character are allowed to evolve at time-dependent or speciation-dependent rates. The final distributions of morphological distance for a given trait among members of a phylad depend on the number of species in the phylad, the rate and pattern of evolution of new character states, and the existence of boundary conditions indicating possible selective constraints on the trait. When morphological change is proportional to time, increasing restrictions on character evolution tend to (a) lower mean distance between species and (b) leave the ratio of mean distances ( DR Dp) in species-rich vs. species-poor phylads of comparable evolutionary age near one. When change is proportional to rate of speciation, similar restrictions tend to (a) limit mean distance only in phylads in which the number of speciations exceeds the range of attainable character states and (b) permit DR Dp to be considerably greater than one, except in extreme cases. Implications of these results for the current phyletic gradualism-rectangular evolution controversy are considered. © 1979

The effect of new biosimilars in rheumatology and gastroenterology specialities on UK healthcare budgets: Results of a budget impact analysis

Background: The approval of new biosimilars of infliximab, etanercept and adalimumab by the European Medicines Agency is expected to produce further cost savings to the healthcare system budget. Objectives: This study aimed to estimate the budget impact of the introduction of new biosimilars Flixabi®, Erelzi®, Solymbic®, Amgevita® and Imraldi® in rheumatology and gastroenterology specialities in the UK. Methods: A published budget impact model was adapted to estimate the expected cost savings following the entry of new biosimilars Flixabi®, Erelzi®, Solymbic®, Amgevita® and Imraldi® in the UK over three-year time horizon. This model was based on retrospective market shares of biologics used in rheumatology and gastroenterology which were derived from DEFINE Software and healthcare professional perspectives. Results: The model predicted that infliximab and etanercept biosimilars would replace their corresponding reference agents by 2020. Adalimumab biosimilars were predicted to achieve 19% of the rheumatology and gastroenterology market by 2020. Without the introduction of further biosimilars, the model predicted a reduction in expenditure of £44 million on biologics over the next three years. With the entry of Flixabi®, Erelzi®, Solymbic®, Amgevita® and Imraldi® the model estimates cumulative savings of £285 million by 2020. Conclusions: The introduction of new infliximab, etanercept and adalimumab biosimilars will be associated with considerable cost savings and have a substantial favourable impact on the UK NHS budget. The number of biosimilars and time of entry of is critical to create competition which will result in maximum cost savings

A novel cell culture model for studying differentiation and apoptosis in the mouse mammary gland.

BACKGROUND: This paper describes the derivation and characterization of a novel, conditionally immortal mammary epithelial cell line named KIM-2. These cells were derived from mid-pregnant mammary glands of a mouse harbouring one to two copies of a transgene comprised of the ovine beta-lactoglobulin milk protein gene promoter, driving expression of a temperature-sensitive variant of simian virus-40 (SV40) large T antigen (T-Ag). RESULTS: KIM-2 cells have a characteristic luminal epithelial cell morphology and a stable, nontransformed phenotype at the semipermissive temperature of 37 degrees C. In contrast, at the permissive temperature of 33 degrees C the cells have an elongated spindle-like morphology and become transformed after prolonged culture. Differentiation of KIM-2 cells at 37 degrees C, in response to lactogenic hormones, results in the formation of polarized dome-like structures with tight junctions. This is accompanied by expression of the milk protein genes that encode beta-casein and whey acidic protein (WAP), and activation of the prolactin signalling molecule, signal transducer and activator of transcription (STAT)5. Fully differentiated KIM-2 cultures at 37 degrees C become dependent on lactogenic hormones for survival and undergo extensive apoptosis upon hormone withdrawal, as indicated by nuclear morphology and flow cytometric analysis. KIM-2 cells can be genetically modified by stable transfection and clonal lines isolated that retain the characteristics of untransfected cells. CONCLUSION: KIM-2 cells are a valuable addition, therefore, to currently available lines of mammary epithelial cells. Their capacity for extensive differentiation in the absence of exogenously added basement membrane, and ability to undergo apoptosis in response to physiological signals will provide an invaluable model system for the study of signal transduction pathways and transcriptional regulatory mechanisms that control differentiation and involution in the mammary gland

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Evaluating the importance of metamorphism in the foundering of continental crust

The metamorphic conditions and mechanisms required to induce foundering in deep arc crust are assessed using an example of representative lower crust in SW New Zealand. Composite plutons of Cretaceous monzodiorite and gabbro were emplaced at ~1.2 and 1.8 GPa are parts of the Western Fiordland Orthogneiss (WFO); examples of the plutons are tectonically juxtaposed along a structure that excised ~25 km of crust. The 1.8 GPa Breaksea Orthogneiss includes suitably dense minor components (e.g. eclogite) capable of foundering at peak conditions. As the eclogite facies boundary has a positive dP/dT, cooling from supra-solidus conditions (T > 950 ºC) at high-P should be accompanied by omphacite and garnet growth. However, a high monzodioritic proportion and inefficient metamorphism in the Breaksea Orthogneiss resulted in its positive buoyancy and preservation. Metamorphic inefficiency and compositional relationships in the 1.2 GPa Malaspina Pluton meant it was never likely to have developed densities sufficiently high to founder. These relationships suggest that the deep arc crust must have primarily involved significant igneous accumulation of garnet–clinopyroxene (in proportions >75%). Crustal dismemberment with or without the development of extensional shear zones is proposed to have induced foundering of excised cumulate material at P > 1.2 GPa

Do cerebrospinal fluid transfer methods affect measured amyloid β42, total tau, and phosphorylated tau in clinical practice?

Introduction Cerebrospinal fluid (CSF) neurodegenerative markers are measured clinically to support a diagnosis of Alzheimer's disease. Several preanalytical factors may alter the CSF concentrations of amyloid β 1–42 (Aβ1–42) in particular with the potential to influence diagnosis. We aimed to determine whether routine handling of samples alters measured biomarker concentration compared with that of prompt delivery to the laboratory. Methods Forty individuals with suspected neurodegenerative diseases underwent diagnostic lumbar punctures using a standardized technique. A sample of each patient's CSF was sent to the laboratory by four different delivery methods: (1) by courier at room temperature; (2) by courier, on ice; (3) using standard hospital portering; and (4) after quarantining for >24 hours. Aβ1–42, total tau (t‐tau), and phosphorylated tau (p‐tau) levels measured using standard enzyme‐linked immunosorbent assay techniques were compared between transfer methods. Results There were no significant differences in Aβ1–42, t‐tau, or p‐tau concentrations measured in samples transported via the different delivery methods despite significant differences in time taken to deliver samples. Discussion When CSF is collected in appropriate tubes, transferred at room temperature, and processed within 24 hours, neurodegenerative markers can be reliably determined

30 days wild: development and evaluation of a large-scale nature engagement campaign to improve well-being

There is a need to increase people’s engagement with and connection to nature, both for human well-being and the conservation of nature itself. In order to suggest ways for people to engage with nature and create a wider social context to normalise nature engagement, The Wildlife Trusts developed a mass engagement campaign, 30 Days Wild. The campaign asked people to engage with nature every day for a month. 12,400 people signed up for 30 Days Wild via an online sign-up with an estimated 18,500 taking part overall, resulting in an estimated 300,000 engagements with nature by participants. Samples of those taking part were found to have sustained increases in happiness, health, connection to nature and pro-nature behaviours. With the improvement in health being predicted by the improvement in happiness, this relationship was mediated by the change in connection to nature