MRL proteins cooperate with activated Ras in glia to drive distinct oncogenic outcomes

The Mig10/RIAM/Lpd (MRL) adapter protein Lpd regulates actin dynamics through interactions with Scar/WAVE and Ena/VASP proteins to promote the formation of cellular protrusions and to stimulate invasive migration. However, the ability of MRL proteins to interact with multiple actin regulators and to promote serum response factor (SRF) signalling has raised the question of whether MRL proteins employ alternative downstream mechanisms to drive oncogenic processes in a context-dependent manner. Here, using a Drosophila model, we show that overexpression of either human Lpd or its Drosophila orthologue Pico can promote growth and invasion of RasV12-induced cell tumours in the brain. Notably, effects were restricted to two populations of Repo-positive glial cells: an invasive population, characterized by JNK-dependent elevation of Mmp1 expression, and a hyperproliferative population lacking elevated JNK signalling. JNK activation was not triggered by reactive immune cell signalling, implicating the involvement of an intrinsic stress response. The ability to promote dissemination of RasV12-induced tumours was shared by a subset of actin regulators, including, most prominently, Chicadee/Profilin, which directly interacts with Pico, and, Mal, a cofactor for serum response factor that responds to changes in G:F actin dynamics. Suppression of Mal activity partially abrogated the ability of pico to promote invasion of RasV12 tumours. Furthermore, we found that larval glia are enriched for serum response factor expression, explaining the apparent sensitivity of glial cells to Pico/RasV12 overexpression. Taken together, our findings indicate that MRL proteins cooperate with oncogenic Ras to promote formation of glial tumours, and that, in this context, Mal/serum response factor activation is rate-limiting for tumour dissemination

Completability and optimal factorization norms in tensor products of Banach function spaces

[EN] Given s-finite measure spaces ( 1, 1, mu 1) and ( 2, 2, mu 2), we consider Banach spaces X1(mu 1) and X2(mu 2), consisting of L0(mu 1) and L0(mu 2) measurable functions respectively, and study when the completion of the simple tensors in the projective tensor product X1(mu 1). p X2(mu 2) is continuously included in the metric space of measurable functions L0(mu 1. mu 2). In particular, we prove that the elements of the completion of the projective tensor product of L p-spaces are measurable functions with respect to the product measure. Assuming certain conditions, we finally showthat given a bounded linear operator T : X1(mu 1). p X2(mu 2). E (where E is a Banach space), a norm can be found for T to be bounded, which is ` minimal' with respect to a given property (2-rectangularity). The same technique may work for the case of n-spaces.J. M. Calabuig and M. Fernandez-Unzueta were supported by Ministerio de Economia, Industria y Competitividad (Spain) under project MTM2014-53009-P. M. Fernandez-Unzueta was also suported by CONACyT 284110. F. Galaz-Fontes was supported by Ministerio de Ciencia e Innovacion (Spain) and FEDER under project MTM2009-14483-C02-01. E. A. Sanchez Perez was supported by Ministerio de Economia, Industria y Competitividad (Spain) and FEDER under project MTM2016-77054-C2-1-P.Calabuig, JM.; Fernández-Unzueta, M.; Galaz-Fontes, F.; Sánchez Pérez, EA. (2019). Completability and optimal factorization norms in tensor products of Banach function spaces. Revista de la Real Academia de Ciencias Exactas Físicas y Naturales Serie A Matemáticas. 113(4):3513-3530. https://doi.org/10.1007/s13398-019-00711-7S351335301134Abramovich, Y.A., Aliprantis, C.D.: An invitation to operator theory. Graduate Studies in Mathematics, Vol 50, AMS (2002)Bennett, C., Sharpley, R.: Interpolation of Operators. Academic Press, Boston (1988)Bu, Q., Buskes, G., Kusraev, A.G.: Bilinear maps on products of vector lattices: a survey. In: Boulabiar, K., Buskes, G., Triki, A. (eds.) Positivity-Trends in Mathematics. Birkhäser Verlag AG, Basel, pp. 97–26 (2007)Buskes, G., Van Rooij, A.: Bounded variation and tensor products of Banach lattices. Positivity 7, 47–59 (2003)Calabuig, J.M., Fernández-Unzueta, M., Galaz-Fontes, F., Sánchez-Pérez, E.A.: Extending and factorizing bounded bilinear maps defined on order continuous Banach function spaces. RACSAM 108(2), 353–367 (2014)Calabuig, J.M., Fernández-Unzueta, M., Galaz-Fontes, F., Sánchez-Pérez, E.A.: Equivalent norms in a Banach function space and the subsequence property. J. Korean Math. Soc. https://doi.org/10.4134/JKMS.j180682Curbera, G.P., Ricker, W.J.: Optimal domains for kernel operators via interpolation. Math. Nachr. 244, 47–63 (2002)Curbera, G.P., Ricker, W.J.: Vector measures, integration and applications. In: Positivity. Birkhäuser Basel, pp. 127–160 (2007)Gil de Lamadrid, J.: Uniform cross norms and tensor products. J. Duke Math. 32, 797–803 (1965)Dunford, N., Schwartz, J.: Linear Operators, Part I: General Theory. Interscience Publishers Inc., New York (1958)Fremlin, D.H.: Tensor products of Archimedean vector lattices. Am. J. Math. 94(3), 777–798 (1972)Fremlin, D.H.: Tensor products of Banach lattices. Math. Ann. 211(2), 87–106 (1974)Yew, K.L.: Completely $$p$$-summing maps on the operator Hilbert space OH. J. Funct. Anal. 255, 1362–1402 (2008)Kwapien, S., Pelczynski, A.: The main triangle projection in matrix spaces and its applications. Stud. Math. 34(1), 43–68 (1970)Lindenstrauss, J., Tzafriri, L.: Classical Banach spaces II. Springer, Berlin (1979)Luxemburg, W.A.J., Zaanen, A.C.: Riesz Spaces I. North-Holland Publishing Company, Amsterdam (1971)Milman, M.: Some new function spaces and their tensor products. Depto. de Matemática, Facultad de Ciencias, U. de los Andes, Mérida, Venezuela (1978)Okada, S., Ricker, W.J., Sánchez Pérez, E.A.: Optimal domain and integral extension of operators acting in function spaces. Oper. Theory Adv. Appl., vol. 180. Birkhäuser, Basel (2008)Schep, A.R.: Factorization of positive multilinear maps. Illinois J. Math. 579–591 (1984)Zaanen, A.C.: Integration. North-Holland Publishing Company, Amsterdam-New York (1967)Zaanen, A.C.: Riesz Spaces II. North-Holland Publishing Company, Amsterdam (1983

Asymptotically faster quantum algorithms to solve multivariate quadratic equations

This paper designs and analyzes a quantum algorithm to solve a system of $m$ quadratic equations in $n$ variables over a finite field ${\bf F}_q$. In the case $m=n$ and $q=2$, under standard assumptions, the algorithm takes time $2^{(t+o(1))n}$ on a mesh-connected computer of area $2^{(a+o(1))n}$, where $t\approx 0.45743$ and $a\approx 0.01467$. The area-time product has asymptotic exponent $t+a\approx 0.47210$. For comparison, the area-time product of Grover\u27s algorithm has asymptotic exponent $0.50000$. Parallelizing Grover\u27s algorithm to reach asymptotic time exponent $0.45743$ requires asymptotic area exponent $0.08514$, much larger than $0.01467$

Effect of formant frequency spacing on perceived gender in pre-pubertal children's voices

<div><p>Background</p><p>It is usually possible to identify the sex of a pre-pubertal child from their voice, despite the absence of sex differences in fundamental frequency at these ages. While it has been suggested that the overall spacing between formants (formant frequency spacing - ΔF) is a key component of the expression and perception of sex in children's voices, the effect of its continuous variation on sex and gender attribution has not yet been investigated.</p><p>Methodology/Principal findings</p><p>In the present study we manipulated voice ΔF of eight year olds (two boys and two girls) along continua covering the observed variation of this parameter in pre-pubertal voices, and assessed the effect of this variation on adult ratings of speakers' sex and gender in two separate experiments. In the first experiment (sex identification) adults were asked to categorise the voice as either male or female. The resulting identification function exhibited a gradual slope from male to female voice categories. In the second experiment (gender rating), adults rated the voices on a continuum from “masculine boy” to “feminine girl”, gradually decreasing their masculinity ratings as ΔF increased.</p><p>Conclusions/Significance</p><p>These results indicate that the role of ΔF in voice gender perception, which has been reported in adult voices, extends to pre-pubertal children's voices: variation in ΔF not only affects the perceived sex, but also the perceived masculinity or femininity of the speaker. We discuss the implications of these observations for the expression and perception of gender in children's voices given the absence of anatomical dimorphism in overall vocal tract length before puberty.</p></div

Sphingosine 1-phosphate modulates antigen capture by murine langerhans cells via the S1P2 receptor subtype

Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P2 receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P2 not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions

Grouping practices in the primary school: what influences change?

During the 1990s, there was considerable emphasis on promoting particular kinds of pupil grouping as a means of raising educational standards. This survey of 2000 primary schools explored the extent to which schools had changed their grouping practices in responses to this, the nature of the changes made and the reasons for those changes. Forty eight percent of responding schools reported that they had made no change. Twenty two percent reported changes because of the literacy hour, 2% because of the numeracy hour, 7% because of a combination of these and 21% for other reasons. Important influences on decisions about the types of grouping adopted were related to pupil learning and differentiation, teaching, the implementation of the national literacy strategy, practical issues and school self-evaluation

Learning about population-health through a community practice learning project: An evaluation study.

Increasing student nurse numbers requiring community placement learning opportunities has led to insufficient numbers of community nurses being available to support student nurses in the community. Although the study presented in the article is based in the UK this issue is reported widely in the literature across the globe. Universities in many countries have had to find innovative ways of providing community health learning opportunities for student nurses. This article reports on how one university in the UK has approached this challenge through students engaging in a population-based study in the community through group work. A research study was undertaken into this innovation which found that the student nurses engaged well with the project and with their groups and undertaking the project had positive value and impact on them and their understanding of population-health. Issues that arose for them largely focused on unequal participation in the group work by some with many participants perceiving that they had done more work on the group project and presentation than others in their group. However, working in this way was perceived to be a good learning experience for the majority of participants

Histidine Hydrogen-Deuterium Exchange Mass Spectrometry for Probing the Microenvironment of Histidine Residues in Dihydrofolate Reductase

Histidine Hydrogen-Deuterium Exchange Mass Spectrometry (His-HDX-MS) determines the HDX rates at the imidazole C(2)-hydrogen of histidine residues. This method provides not only the HDX rates but also the pK(a) values of histidine imidazole rings. His-HDX-MS was used to probe the microenvironment of histidine residues of E. coli dihydrofolate reductase (DHFR), an enzyme proposed to undergo multiple conformational changes during catalysis.Using His-HDX-MS, the pK(a) values and the half-lives (t(1/2)) of HDX reactions of five histidine residues of apo-DHFR, DHFR in complex with methotrexate (DHFR-MTX), DHFR in complex with MTX and NADPH (DHFR-MTX-NADPH), and DHFR in complex with folate and NADP+ (DHFR-folate-NADP+) were determined. The results showed that the two parameters (pK(a) and t(1/2)) are sensitive to the changes of the microenvironment around the histidine residues. Although four of the five histidine residues are located far from the active site, ligand binding affected their pK(a), t(1/2) or both. This is consistent with previous observations of ligand binding-induced distal conformational changes on DHFR. Most of the observed pK(a) and t(1/2) changes could be rationalized using the X-ray structures of apo-DHFR, DHFR-MTX-NADPH, and DHFR-folate-NADP+. The availability of the neutron diffraction structure of DHFR-MTX enabled us to compare the protonation states of histidine imidazole rings.Our results demonstrate the usefulness of His-HDX-MS in probing the microenvironments of histidine residues within proteins

A prospective cohort study assessing clinical referral management & workforce allocation within a UK regional medical genetics service

Abstract Ensuring patient access to genomic information in the face of increasing demand requires clinicians to develop innovative ways of working. This paper presents the first empirical prospective observational cohort study of UK multi-disciplinary genetic service delivery. It describes and explores collaborative working practices including the utilisation and role of clinical geneticists and non-medical genetic counsellors. Six hundred and fifty new patients referred to a regional genetics service were tracked through 850 clinical contacts until discharge. Referral decisions regarding allocation of lead health professional assigned to the case were monitored, including the use of initial clinical contact guidelines. Significant differences were found in the cases led by genetic counsellors and those led by clinical geneticists. Around a sixth, 16.8% (109/650) of referrals were dealt with by a letter back to the referrer or re-directed to another service provider and 14.8% (80/541) of the remaining patients chose not to schedule an appointment. Of the remaining 461 patients, genetic counsellors were allocated as lead health professional for 46.2% (213/461). A further 61 patients did not attend. Of those who did, 86% (345/400) were discharged after one or two appointments. Genetic counsellors contributed to 95% (784/825) of total patient contacts. They provided 93.7% (395/432) of initial contacts and 26.8% (106/395) of patients were discharged at that point. The information from this study informed a planned service re-design. More research is needed to assess the effectiveness and efficiency of different models of collaborative multi-disciplinary working within genetics services. Keywords (MeSH terms) Genetic Services, Genetic Counseling, Interdisciplinary Communication, Cohort Studies, Delivery of Healthcare, Referral and Consultation

N-acetylgalactosaminyl transferase-3 is a potential new marker for non-small cell lung cancers

N-acetylgalactosaminyl transferase-3 (GalNAc-T3) is an enzyme involved in the initial glycosylation of mucin-type O-linked proteins. In the present study, we used immunohistochemistry to examine GalNAc-T3 expression in 215 surgically resected non-small cell lung cancers. We analysed the biological and clinical importance of GalNAc-T3 expression, especially with regard to its potential as a prognostic factor. We found that normal bronchial epithelial cells, bronchial gland cells, and alveolar pneumocytes showed cytoplasmic immunostaining for GalNAc-T3. Low expression of GalNAc-T3, observed in 93 of 215 tumours (43.4%), was found more frequently in tumours from smokers than those from nonsmokers (P=0.001), in squamous cell carcinomas than nonsquamous cell carcinomas (P<0.0001), and in moderately and poorly differentiated tumours than well differentiated tumours (P=0.0002). Multivariate logistic regression analysis showed that an association of low GalNAc-T3 expression with squamous cell carcinomas was the only one significant relationship of GalNAc-T3 expression with various factors (P<0.0001). Moreover, tumours losing GalNAc-T3 expression had a significantly higher Ki-67 labelling index than tumours retaining GalNAc-T3 expression (P=0.0003). Patients with low GalNAc-T3 expression survived a significantly shorter time than patients with high GalNAc-T3 expression in 103 pStage I non-small cell lung cancers (5-year survival rates, 58% and 78%, respectively; P=0.02 by log-rank test) as well as in 61 pStage I nonsquamous cell carcinomas (5-year survival rates, 63% and 85%, respectively; P=0.03). Low GalNAc-T3 expression was an unfavourable prognostic factor in pStage I non-small cell lung cancers (hazards ratio, 2.04; P=0.03), and in pStage I nonsquamous cell carcinomas (hazards ratio, 2.70; P=0.03). These results suggest that GalNAc-T3 is a new marker of non-small cell lung cancers with specificity for histology and prognosis