Fos co-operation with PTEN loss elicits keratoacanthoma not carcinoma due to p53/p21^WAF-induced differentiation triggered by GSK3b inactivation and reduced AKT activity

To investigate gene synergism in multistage skin carcinogenesis, the RU486-inducible cre/lox system was employed to ablate PTEN function [K14.cre/D5PTENflx] in mouse epidermis expressing activated v-fos [HK1.fos]. RU486-treated HK1.fos/D5PTENflx mice exhibited hyperplasia, hyperkeratosis and tumours that progressed to highly differentiated keratoacanthomas rather than carcinomas, due to re-expression of high p53 and p21WAF levels. Despite elevated MAP kinase activity, cyclin D1/E2 over expression and increased AKT activity forming areas of highly proliferative, papillomatous keratinocytes, increasing levels of GSK3b inactivation exceeded a threshold that induced p53/p21WAF expression to halt proliferation and accelerate differentiation, giving the hallmark keratosis of keratoacanthomas. A pivotal facet to this GSK3b-triggered mechanism centred on increasing p53 expression in basal layer keratinocytes. This reduced activated AKT expression and released inhibition of p21WAF, which accelerated keratinocyte differentiation, as indicated by unique basal layer expression of differentiation-specific keratin K1, alongside premature filaggrin and loricrin expression. Thus, fos synergism with PTEN loss elicited a benign tumour context where GSK3b-induced, p53/p21WAF expression continually switched AKT-associated proliferation into one of differentiation, preventing further progression. This putative compensatory mechanism required the critical availability of normal p53 and/or p21WAF otherwise deregulated fos, Akt and GSK3b associate with malignant progression

Mechanically induced current and quantum evaporation from Luttinger liquids

We investigate transport through a tunnelling junction between an uncorrelated metallic lead and a Luttinger liquid when the latter is subjected to a time dependent perturbation. The tunnelling current as well as the electron energy distribution function are found to be strongly affected by the perturbation due to generation of harmonics in the density oscillations. Using a semiconducting lead instead of a metallic one results in electrons being injected into the lead even without applied voltage. Some applications to carbon nanotubes are discussed.Comment: 7 pages, 2 figures (eps files

Concurrent stochastic methods for global optimization

The global optimization problem, finding the lowest minimizer of a nonlinear function of several variables that has multiple local minimizers, appears well suited to concurrent computation. This paper presents a new parallel algorithm for the global optimization problem. The algorithm is a stochastic method related to the multi-level single-linkage methods of Rinnooy Kan and Timmer for sequential computers. Concurrency is achieved by partitioning the work of each of the three main parts of the algorithm, sampling, local minimization start point selection, and multiple local minimizations, among the processors. This parallelism is of a coarse grain type and is especially well suited to a local memory multiprocessing environment. The paper presents test results of a distributed implementation of this algorithm on a local area network of computer workstations. It also summarizes the theoretical properties of the algorithm

A weakly coupled semiconductor superlattice as a harmonic hypersonic-electrical transducer

We study experimentally and theoretically the effects of high-frequency strain pulse trains on the charge transport in a weakly coupled semiconductor superlattice. In a frequency range of the order of 100 GHz such excitation may be considered as single harmonic hypersonic excitation. While travelling along the axis of the SL, the hypersonic acoustic wavepacket affects the electron tunnelling, and thus governs the electrical current through the device. We reveal how the change of current depends on the parameters of the hypersonic excitation and on the bias applied to the superlattice. We have found that the changes in the transport properties of the superlattices caused by the acoustic excitation can be largely explained using the current-voltage relation of the unperturbed system. Our experimental measurements show multiple peaks in the dependence of the transferred charge on the repetition rate of the strain pulses in the train. We demonstrate that these resonances can be understood in terms of the spectrum of the applied acoustic perturbation after taking into account the multiple reflections in the metal film serving as a generator of hypersonic excitation. Our findings suggest an application of the semiconductor superlattice as a hypersonic-electrical transducer, which can be used in various microwave devices

Filamentary mass accretion towards the high-mass protobinary system G11.92-0.61 MM2

Funding: S.Z. is funded by the China Scholarship Council-University of St Andrews Scholarship (PhD programmes, No. 201806190010). C.J.C. acknowledges support from the University of St Andrews Restarting Research Funding Scheme (SARRF), which is funded through the SFC grant reference SFC/AN/08/020. J.D.H gratefully acknowledges financial support from the Royal Society (University Research Fellowship; URF\R1\2216.We present deep, sub-arcsecond (∼2000 AU) resolution ALMA 0.82 mm observations of the former high-mass prestellar core candidate G11.92-0.61 MM2, recently shown to be an ~500 AU-separation protobinary. Our observations show that G11.92-0.61 MM2, located in the G11.92-0.61 protocluster, lies on a filamentary structure traced by 0.82 mm continuum and N2H+(4-3) emission. The N2H+(4-3) spectra are multi-peaked, indicative of multiple velocity components along the line of sight. To analyse the gas kinematics, we performed pixel-by-pixel Gaussian decomposition of the N2H+$ spectra using SCOUSEPY and hierarchical clustering of the extracted velocity components using ACORNS. Seventy velocity- and position-coherent clusters (called "trees") are identified in the N2H+-emitting gas, with the 8 largest trees accounting for > 60 per cent  of the fitted velocity components. The primary tree, with ~20 per cent of the fitted velocity components, displays a roughly north-south velocity gradient along the filamentary structure traced by the 0.82 mm continuum. Analysing a ~0.17 pc-long substructure, we interpret its velocity gradient of ~10.5 km s-1pc-1 as tracing filamentary accretion towards MM2 and estimate a mass inflow rate of ~1.8 × 10-4 to 1.2 × 10-3 M⊙ yr-1. Based on the recent detection of a bipolar molecular outflow associated with MM2, accretion onto the protobinary is ongoing, likely fed by the larger-scale filamentary accretion flows. If 50% of the filamentary inflow reaches the protostars, each member of the protobinary would attain a mass of 8 M⊙ within ~1.6 × 105 yr, comparable to the combined timescale of the 70-μm- and mid-infrared-weak phases derived for ATLASGAL-TOP100 massive clumps using chemical clocks.Peer reviewe

Lost in translation? Standardising the terminology used in marine invasion biology and updating South African alien species lists

Confusion between terms and ambiguities among definitions have long plagued the field of invasion biology. One result is disruption in flow of information from researchers to policy-makers and managers who rely on science to inform regulatory frameworks and management actions. We reviewed the South African marine biology literature to quantify the current usage of terminology describing marine invasions and found a variety of terms in use, few of which are defined when used. In response, we propose standard terminology that aligns with international practice. We then interpreted the Blackburn unified framework for biological invasions within the marine context and used this as a transparent way to apply the standardised terms to an updated list of marine alien species for the country. This resulted in the recognition of 36 alien and 53 invasive species within South Africa. Most notably, follow-up research is required to confirm the status of at least 11 listed species, the majority of which have been recorded only once, or not in the past 25 years. It is hoped that by standardising terminology, marine science in South Africa will better support authorities charged with managing the threat posed by marine alien species

Interacting one dimensional electron gas with open boundaries

We discuss the properties of interacting electrons on a finite chain with open boundary conditions. We extend the Haldane Luttinger liquid description to these systems and study how the presence of the boundaries modifies various correlation functions. In view of possible experimental applications to quantum wires, we analyse how tunneling measurements can reveal the underlying Luttinger liquid properties. The two terminal conductance is calculated. We also point out possible applications to quasi one dimensional materials and study the effects of magnetic impurities.Comment: 38 pages, ReVTeX, 7 figures (available upon request

The UNC-Wisconsin rhesus macaque neurodevelopment database: A structural MRI and DTI database of early postnatal development

Rhesus macaques are commonly used as a translational animal model in neuroimaging and neurodevelopmental research. In this report, we present longitudinal data from both structural and diffusion MRI images generated on a cohort of 34 typically developing monkeys from 2 weeks to 36 months of age. All images have been manually skull stripped and are being made freely available via an online repository for use by the research community

A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS- mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CA E545K mutation as conferring drug resistance. We demonstrate that PIK3CA E545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA E545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CA E545K -induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. SIGNIFICANCE: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CA E545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CA E545K -expressing NRAS-mutant melanoma cells to MEKi + CDK4i. © 2018 AAC