The actin-myosin regulatory MRCK kinases: regulation, biological functions and associations with human cancer

The contractile actin-myosin cytoskeleton provides much of the force required for numerous cellular activities such as motility, adhesion, cytokinesis and changes in morphology. Key elements that respond to various signal pathways are the myosin II regulatory light chains (MLC), which participate in actin-myosin contraction by modulating the ATPase activity and consequent contractile force generation mediated by myosin heavy chain heads. Considerable effort has focussed on the role of MLC kinases, and yet the contributions of the myotonic dystrophy-related Cdc42-binding kinases (MRCK) proteins in MLC phosphorylation and cytoskeleton regulation have not been well characterized. In contrast to the closely related ROCK1 and ROCK2 kinases that are regulated by the RhoA and RhoC GTPases, there is relatively little information about the CDC42-regulated MRCKα, MRCKβ and MRCKγ members of the AGC (PKA, PKG and PKC) kinase family. As well as differences in upstream activation pathways, MRCK and ROCK kinases apparently differ in the way that they spatially regulate MLC phosphorylation, which ultimately affects their influence on the organization and dynamics of the actin-myosin cytoskeleton. In this review, we will summarize the MRCK protein structures, expression patterns, small molecule inhibitors, biological functions and associations with human diseases such as cancer

Anxiety and self-esteem as mediators of the relation between family communication and indecisiveness in adolescence

Abstract In this study, we explored the unique and common contributions of anxiety, self-esteem, and family communication on indecisiveness among adolescents. Three hundred and fifty pupils from 13 to 16 years of age completed selfreport measures on indecisiveness, quality of family communication, trait anxiety, and self-esteem. The findings in this study showed that students\u2019 indecisiveness is predicted by family communication mediated by anxiety and self-esteem. These results have important implications for practice as it stresses the importance of anxiety and self-esteem. Nevertheless, the counselors could also focus on enhancing relationship-building skills by introducing the adolescents\u2019 career formation as an adolescent\u2013parent joint project.L\u2019anxie\ub4te\ub4 et l\u2019estime de soi comme me\ub4diateurs de la relation entre communication au sein de la famille et indecision chronique a` l\u2019adolescence. Dans cette e\ub4tude, nous avons explore\ub4 les contributions uniques et communes de l\u2019anxiete\ub4, de l\u2019estime de soi et de la communication au sein de la famille sur l\u2019indecision chronique aupres d\u2019adolescents. Trois cent cinquante e\ub4le`ves a\u2c6ge\ub4s de 13 a` 16 ans ont rempli des mesures d\u2019auto-e\ub4valuation de l\u2019inde\ub4cision chronique, de la qualite\ub4 de la communication familiale, de l\u2019anxie\ub4te\ub4-trait et de l\u2019estime de soi. Les re\ub4sultats de cette e\ub4tude ont montre\ub4 que l\u2019inde\ub4cision des e\ub4tudiants est explique\ub4e par la communication au sein de la famille et que ce lien est me\ub4diatise\ub4 par l\u2019anxie\ub4te\ub4 et l\u2019estime de soi. Ces re\ub4sultats ont des implications importantes pour la pratique car ils soulignent l\u2019importance de l\u2019anxie\ub4te\ub4 et l\u2019estime de soi. Ne\ub4anmoins, les conseillers pourraient e\ub4galement se concentrer sur l\u2019ame\ub4lioration des compe\ub4tences de construction relationnelle en introduisant la formation professionnelle des adolescents comme un projet conjoint adolescent-parent.Resumen. Ansiedad y Autoestima como Mediadores de la Relacio\ub4n entre Comunicacio\ub4n Familiar e Indecisio\ub4n en la Adolescencia. En este estudio, exploramos las contribuciones u\ub4nicas y comunes de la ansiedad, la autoestima y la comunicacio\ub4n de familia en la indecisio\ub4n de los adolescentes. Tres y cientos cincuenta alumnos entre los 13 y 16 an\u2dcos completaron auto-evaluaciones sobre la indecisio\ub4n, la calidad de comunicacio\ub4n familiar, los rasgos de ansiedad y la autoestima. Los resultados en este estudio muestran que la indecisio\ub4n en los estudiantes es prevista por la comunicacio\ub4n familiar mediada por la ansiedad y la autoestima. Estos resultados tiene importantes implicaciones para la practica ya que destacan la importancia de la ansiedad y la autoestima. Sin embargo, los consejeros podr\u131\ub4an tambie\ub4n focalizarse en el aumento de sus habilidades para construir relaciones mediante la introduccio\ub4n de la formacio\ub4n profesional para adolescentes como un proyecto conjunto del adolescente-padre.Angst und Selbstwertgefu\ua8 hl als Mediatoren der Beziehung zwischen Kommunikation in der Familie und Unentschlossenheit in der Adoleszenz. In dieser Studie untersuchten wir die spezifischen und gemeinsamen Beitra\ua8ge von Angst, Selbstwertgefu\ua8hl und Kommunikation in der Familie auf Unentschlossenheit unter Jugendlichen. Dreihundertfu\ua8nfzig Schu\ua8ler, zwischen 13 bis 16 Jahre alt, fu\ua8llten Skalen zur Unentschlossenheit, Qualita\ua8t der Kommunikation in der Familie, A\ua8 ngstlichkeit und Selbstwertgefu\ua8hl aus. Die Ergebnisse dieser Studie zeigten, dass Unentschlossenheit der Schu\ua8ler von Kommunikation in der Familie vorhergesagt wird, vermittelt durch Angst und Selbstwertgefu\ua8 hl. Diese Ergebnisse haben wichtige Implikationen fu\ua8r die Praxis, da sie die Bedeutung von Angst und Selbstwertgefu\ua8hl hervorheben. Dennoch ko\ua8nnten sich die Beratungspersonen durch die Einfu\ua8hrung der beruflichen Bildung der Jugendlichen als ein gemeinsames Projekt von Jugendliche-Elternteil auch auf die Verbesserung der Fa\ua8higkeiten zum Aufbau von Beziehungen konzentrieren

Standards for data acquisition and software‐based analysis of in vivo electroencephalography recordings from animals. A TASK1‐WG5 report of the AES/ILAE Translational Task Force of the ILAE

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139127/1/epi13909.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139127/2/epi13909_am.pd

Bilateral macular hole formation secondary to sclopetaria caused by shockwaves transmitted by a posterior vector: case report

<p>Abstract</p> <p>Background</p> <p>Sclopetaria is a rare ophthalmic finding in trauma</p> <p>Case Presentation</p> <p>This is a report of a patient who developed macular holes from sclopetaria induced by indirect trauma. A 22-year-old male, suffered a gunshot wound that passed behind his eyes, resulting in bilateral macular hole formation</p> <p>Conclusion</p> <p>To our knowledge, this is the first reported case in which trauma posterior to the globes caused bilateral macular hole formation</p

Co-Crystal Structures of Inhibitors with MRCKβ, a Key Regulator of Tumor Cell Invasion

MRCKα and MRCKβ (myotonic dystrophy kinase-related Cdc42-binding kinases) belong to a subfamily of Rho GTPase activated serine/threonine kinases within the AGC-family that regulate the actomyosin cytoskeleton. Reflecting their roles in myosin light chain (MLC) phosphorylation, MRCKα and MRCKβ influence cell shape and motility. We report further evidence for MRCKα and MRCKβ contributions to the invasion of cancer cells in 3-dimensional matrix invasion assays. In particular, our results indicate that the combined inhibition of MRCKα and MRCKβ together with inhibition of ROCK kinases results in significantly greater effects on reducing cancer cell invasion than blocking either MRCK or ROCK kinases alone. To probe the kinase ligand pocket, we screened 159 kinase inhibitors in an in vitro MRCKβ kinase assay and found 11 compounds that inhibited enzyme activity >80% at 3 µM. Further analysis of three hits, Y-27632, Fasudil and TPCA-1, revealed low micromolar IC50 values for MRCKα and MRCKβ. We also describe the crystal structure of MRCKβ in complex with inhibitors Fasudil and TPCA-1 bound to the active site of the kinase. These high-resolution structures reveal a highly conserved AGC kinase fold in a typical dimeric arrangement. The kinase domain is in an active conformation with a fully-ordered and correctly positioned αC helix and catalytic residues in a conformation competent for catalysis. Together, these results provide further validation for MRCK involvement in regulation of cancer cell invasion and present a valuable starting point for future structure-based drug discovery efforts

Long-lived magnetism from solidification-driven convection on the pallasite parent body.

Palaeomagnetic measurements of meteorites suggest that, shortly after the birth of the Solar System, the molten metallic cores of many small planetary bodies convected vigorously and were capable of generating magnetic fields. Convection on these bodies is currently thought to have been thermally driven, implying that magnetic activity would have been short-lived. Here we report a time-series palaeomagnetic record derived from nanomagnetic imaging of the Imilac and Esquel pallasite meteorites, a group of meteorites consisting of centimetre-sized metallic and silicate phases. We find a history of long-lived magnetic activity on the pallasite parent body, capturing the decay and eventual shutdown of the magnetic field as core solidification completed. We demonstrate that magnetic activity driven by progressive solidification of an inner core is consistent with our measured magnetic field characteristics and cooling rates. Solidification-driven convection was probably common among small body cores, and, in contrast to thermally driven convection, will have led to a relatively late (hundreds of millions of years after accretion), long-lasting, intense and widespread epoch of magnetic activity among these bodies in the early Solar System.The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement No. 320750, the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 312284, the Natural Environment Research Council, Fundación ARAID and the Spanish MINECO MAT2011-23791.This is the accepted manuscript. The final version is available from Nature at http://www.nature.com/nature/journal/v517/n7535/full/nature14114.html

Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome

Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity is an inborn error of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of the enzymatic deficiency. The prevalence is estimated at 1/380,000 live births in Canada, and 1/235,000 live births in Spain. Uric acid overproduction is present inall HPRT-deficient patients and is associated with lithiasis and gout. Neurological manifestations include severe action dystonia, choreoathetosis, ballismus, cognitive and attention deficit, and self-injurious behaviour. The most severe forms are known as Lesch-Nyhan syndrome (patients are normal at birth and diagnosis can be accomplished when psychomotor delay becomes apparent). Partial HPRT-deficient patients present these symptoms with a different intensity, and in the least severe forms symptoms may be unapparent. Megaloblastic anaemia is also associated with the disease. Inheritance of HPRT deficiency is X-linked recessive, thus males are generally affected and heterozygous female are carriers (usually asymptomatic). Human HPRT is encoded by a single structural gene on the long arm of the X chromosome at Xq26. To date, more than 300 disease-associated mutations in the HPRT1 gene have been identified. The diagnosis is based on clinical and biochemical findings (hyperuricemia and hyperuricosuria associated with psychomotor delay), and enzymatic (HPRT activity determination in haemolysate, intact erythrocytes or fibroblasts) and molecular tests. Molecular diagnosis allows faster and more accurate carrier and prenatal diagnosis. Prenatal diagnosis can be performed with amniotic cells obtained by amniocentesis at about 15–18 weeks' gestation, or chorionic villus cells obtained at about 10–12 weeks' gestation. Uric acid overproduction can be managed by allopurinol treatment. Doses must be carefully adjusted to avoid xanthine lithiasis. The lack of precise understanding of the neurological dysfunction has precluded development of useful therapies. Spasticity, when present, and dystonia can be managed with benzodiazepines and gamma-aminobutyric acid inhibitors such as baclofen. Physical rehabilitation, including management of dysarthria and dysphagia, special devices to enable hand control, appropriate walking aids, and a programme of posture management to prevent deformities are recommended. Self-injurious behaviour must be managed by a combination of physical restraints, behavioural and pharmaceutical treatments

Being there: a preliminary study examining the role of presence in Internet Gaming Disorder

Internet Gaming Disorder (IGD) has been introduced as an emerging mental health condition requiring further study. Associations between IGD and gaming presence (i.e., absorption in the virtual environment) have been implied. The aim of the present study was twofold: (a) to evaluate the extent to which presence contributes to IGD severity and, (b) to examine longitudinal differences in IGD according to the initial level of presence experienced. The participants comprising 125 emerging adults aged 18 to 29 years completed either: (i) three face-to-face assessments (one month apart, over three months) or (ii) a cross-sectional, online assessment. IGD was assessed with the nine-item IGD Scale Short Form and presence was assessed using the Presence Questionnaire. Regression and latent growth modelling analyses were conducted. Findings demonstrated that the level of gaming presence related to IGD severity but not to linear change in severity over a three-month period. The study shows that emergent adults who play internet games may be at a high risk of IGD given a more salient sense of being present within the gaming environment. Clinical implications considering prevention and intervention initiatives are discussed

A nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female survivors of childhood cancer: design and methodological challenges

<p>Abstract</p> <p>Background</p> <p>Advances in childhood cancer treatment over the past decades have significantly improved survival, resulting in a rapidly growing group of survivors. However, both chemo- and radiotherapy may adversely affect reproductive function. This paper describes the design and encountered methodological challenges of a nationwide study in the Netherlands investigating the effects of treatment on reproductive function, ovarian reserve, premature menopause and pregnancy outcomes in female childhood cancer survivors (CCS), the DCOG LATER-VEVO study.</p> <p>Methods</p> <p>The study is a retrospective cohort study consisting of two parts: a questionnaire assessing medical, menstrual, and obstetric history, and a clinical assessment evaluating ovarian and uterine function by hormonal analyses and transvaginal ultrasound measurements. The eligible study population consists of adult female 5-year survivors of childhood cancer treated in the Netherlands, whereas the control group consists of age-matched sisters of the participating CCS. To date, study invitations have been sent to 1611 CCS and 429 sister controls, of which 1215 (75%) and 333 (78%) have responded so far. Of these responders, the majority consented to participate in both parts of the study (53% vs. 65% for CCS and sister controls respectively). Several challenges were encountered involving the study population: dealing with bias due to the differences in characteristics of several types of (non-) participants and finding an adequately sized and well-matched control group. Moreover, the challenges related to the data collection process included: differences in response rates between web-based and paper-based questionnaires, validity of self-reported outcomes, interpretation of clinical measurements of women using hormonal contraceptives, and inter- and intra-observer variation of the ultrasound measurements.</p> <p>Discussion</p> <p>The DCOG LATER-VEVO study will provide valuable information about the reproductive potential of paediatric cancer patients as well as long-term survivors of childhood cancer. Other investigators planning to conduct large cohort studies on late effects may encounter similar challenges as those encountered during this study. The solutions to these challenges described in this paper may be useful to these investigators.</p> <p>Trial registration</p> <p>NTR2922; <url>http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922</url></p

Learning to Use Illumination Gradients as an Unambiguous Cue to Three Dimensional Shape

The luminance and colour gradients across an image are the result of complex interactions between object shape, material and illumination. Using such variations to infer object shape or surface colour is therefore a difficult problem for the visual system. We know that changes to the shape of an object can affect its perceived colour, and that shading gradients confer a sense of shape. Here we investigate if the visual system is able to effectively utilise these gradients as a cue to shape perception, even when additional cues are not available. We tested shape perception of a folded card object that contained illumination gradients in the form of shading and more subtle effects such as inter-reflections. Our results suggest that observers are able to use the gradients to make consistent shape judgements. In order to do this, observers must be given the opportunity to learn suitable assumptions about the lighting and scene. Using a variety of different training conditions, we demonstrate that learning can occur quickly and requires only coarse information. We also establish that learning does not deliver a trivial mapping between gradient and shape; rather learning leads to the acquisition of assumptions about lighting and scene parameters that subsequently allow for gradients to be used as a shape cue. The perceived shape is shown to be consistent for convex and concave versions of the object that exhibit very different shading, and also similar to that delivered by outline, a largely unrelated cue to shape. Overall our results indicate that, although gradients are less reliable than some other cues, the relationship between gradients and shape can be quickly assessed and the gradients therefore used effectively as a visual shape cue