Towards in vivo g-ratio mapping using MRI: unifying myelin and diffusion imaging

The g-ratio, quantifying the comparative thickness of the myelin sheath encasing an axon, is a geometrical invariant that has high functional relevance because of its importance in determining neuronal conduction velocity. Advances in MRI data acquisition and signal modelling have put in vivo mapping of the g-ratio, across the entire white matter, within our reach. This capacity would greatly increase our knowledge of the nervous system: how it functions, and how it is impacted by disease. This is the second review on the topic of g-ratio mapping using MRI. As such, it summarizes the most recent developments in the field, while also providing methodological background pertinent to aggregate g-ratio weighted mapping, and discussing pitfalls associated with these approaches. Using simulations based on recently published data, this review demonstrates the relevance of the calibration step for three myelin-markers (macromolecular tissue volume, myelin water fraction, and bound pool fraction). It highlights the need to estimate both the slope and offset of the relationship between these MRI-based markers and the true myelin volume fraction if we are really to achieve the goal of precise, high sensitivity g-ratio mapping in vivo. Other challenges discussed in this review further evidence the need for gold standard measurements of human brain tissue from ex vivo histology. We conclude that the quest to find the most appropriate MRI biomarkers to enable in vivo g-ratio mapping is ongoing, with the potential of many novel techniques yet to be investigated.Comment: Will be published as a review article in Journal of Neuroscience Methods as parf of the Special Issue with Hu Cheng and Vince Calhoun as Guest Editor

Multidimensional Localized Solitons

Recently it has been discovered that some nonlinear evolution equations in 2+1 dimensions, which are integrable by the use of the Spectral Transform, admit localized (in the space) soliton solutions. This article briefly reviews some of the main results obtained in the last five years thanks to the renewed interest in soliton theory due to this discovery. The theoretical tools needed to understand the unexpected richness of behaviour of multidimensional localized solitons during their mutual scattering are furnished. Analogies and especially discrepancies with the unidimensional case are stressed

A transcriptional regulatory mechanism finely tunes the firing of type VI secretion system in response to bacterial enemies

The ability to detect and measure danger from an environmental signal is paramount for bacteria to respond accordingly, deploying strategies that halt or counteract potential cellular injury and maximize survival chances. Type VI secretion systems (T6SSs) are complex bacterial contractile nanomachines able to target toxic effectors into neighboring bacteria competing for the same colonization niche. Previous studies support the concept that either T6SSs are constitutively active or they fire effectors in response to various stimuli, such as high bacterial density, cell-cell contact, nutrient depletion, or components from dead sibling cells. For Serratia marcescens, it has been proposed that its T6SS is stochastically expressed, with no distinction between harmless or aggressive competitors. In contrast, we demonstrate that the Rcs regulatory system is responsible for finely tuning Serratia T6SS expression levels, behaving as a transcriptional rheostat. When confronted with harmless bacteria, basal T6SS expression levels suffice for Serratia to eliminate the competitor. A moderate T6SS upregulation is triggered when, according to the aggressor-prey ratio, an unbalanced interplay between homologous and heterologous effectors and immunity proteins takes place. Higher T6SS expression levels are achieved when Serratia is challenged by a contender like Acinetobacter, which indiscriminately fires heterologous effectors able to exert lethal cellular harm, threatening the survival of the Serratia population. We also demonstrate that Serratia’s RcsB-dependent T6SS regulatory mechanism responds not to general stress signals but to the action of specific effectors from competitors, displaying an exquisite strategy to weigh risks and keep the balance between energy expenditure and fitness costs. IMPORTANCE Serratia marcescens is among the health-threatening pathogens categorized by the WHO as research priorities to develop alternative antimicrobial strategies, and it was also recently identified as one major component of the gut microbiome in familial Crohn disease dysbiosis. Type VI secretion systems (T6SSs) stand among the array of survival strategies that Serratia displays. They are contractile multiprotein complexes able to deliver toxic effectors directed to kill bacterial species sharing the same niche and, thus, competing for vital resources. Here, we show that Serratia is able to detect and measure the extent of damage generated through T6SS-delivered toxins from neighboring bacteria and responds by transcriptionally adjusting the expression level of its own T6SS machinery to counterattack the rival. This strategy allows Serratia to finely tune the production of costly T6SS devices to maximize the chances of successfully fighting against enemies and minimize energy investment. The knowledge of this novel mechanism provides insight to better understand bacterial interactions and design alternative treatments for polymicrobial infections.Fil: Lazzaro, Martina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Feldman, Mario F.. Washington University in St. Louis; Estados UnidosFil: Garcia Vescovi, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentin

Increasing the lensing figure of merit through higher order convergence moments

The unprecedented quality, the increased data set, and the wide area of ongoing and near future weak lensing surveys allows one to move beyond the standard two points statistics, thus making it worthwhile to investigate higher order probes. As an interesting step toward this direction, we explore the use of higher order moments (HOM) of the convergence field as a way to increase the lensing figure of merit (FoM). To this end, we rely on simulated convergence to first show that HOM can be measured and calibrated so that it is indeed possible to predict them for a given cosmological model provided suitable nuisance parameters are introduced and then marginalized over. We then forecast the accuracy on cosmological parameters from the use of HOM alone and in combination with standard shear power spectra tomography. It turns out that HOM allow one to break some common degeneracies, thus significantly boosting the overall FoM. We also qualitatively discuss possible systematics and how they can be dealt with

Action of HMGB1 on miR221/222 cluster in neuroblastoma cell lines

microRNA (miR/miRNA) are small non-coding RNAs that control gene expression at the post-transcriptional level by targeting mRNAs. Aberrant expression of miRNAs is often observed in different types of cancer. Specific miRNAs function as tumor suppressors or oncogenes and interfere with various aspects of carcinogenesis, including differentiation, proliferation and invasion. Upregulation of miRNAs 221 and 222 has been shown to induce a malignant phenotype in numerous human cancers via inhibition of phosphatase and tensin homolog (PTEN) expression. Neuroblastoma is the most common extracranial solid malignancy in children, which is characterized by cellular heterogeneity that corresponds to different clinical outcomes. The different cellular phenotypes are associated with different gene mutations and miRs that control genetic and epigenetic factors. For this reason miRs are considered a potential therapeutic target in neuroblastoma. The aim of the present study was to investigate the mechanisms by which extracellular high mobility group box 1 (HMGB1) promotes cell growth in neuroblastoma. SK-N-BE(2) and SH-SY5Y neuroblastoma derived cell lines were transfected with the antisense oligonucleotides, anti-miR-221 and -222, followed by treatment with HMGB1 to investigate the expression of the oncosuppressor PTEN. In this study, it was demonstrated that HMGB1, which is released by damaged cells and tumor cells, upregulates miR-221/222 oncogenic clusters in the two human neuroblastoma derived cell lines. The results revealed that the oncogenic cluster miRs 221/222 were more highly expressed by the most undifferentiated cell line [SK-N-BE(2)] compared with the the less tumorigenic cell line (SH-SY5Y) and that exogenous HMGB1 increases this expression. In addition, HMGB1 modulates PTEN expression via miR-221/222, as demonstrated by transiently blocking miR-221/222 with anti-sense oligonucleotides. These results may lead to the development of novel therapeutic strategies for neuroblastoma

Abelian Chern-Simons Vortices and Holomorphic Burgers' Hierarchy

The Abelian Chern-Simons Gauge Field Theory in 2+1 dimensions and its relation with holomorphic Burgers' Hierarchy is considered. It is shown that the relation between complex potential and the complex gauge field as in incompressible and irrotational hydrodynamics, has meaning of the analytic Cole-Hopf transformation, linearizing the Burgers Hierarchy in terms of the holomorphic Schr\"odinger Hierarchy. Then the motion of planar vortices in Chern-Simons theory, appearing as pole singularities of the gauge field, corresponds to motion of zeroes of the hierarchy. Using boost transformations of the complex Galilean group of the hierarchy, a rich set of exact solutions, describing integrable dynamics of planar vortices and vortex lattices in terms of the generalized Kampe de Feriet and Hermite polynomials is constructed. The results are applied to the holomorphic reduction of the Ishimori model and the corresponding hierarchy, describing dynamics of magnetic vortices and corresponding lattices in terms of complexified Calogero-Moser models. Corrections on two vortex dynamics from the Moyal space-time non-commutativity in terms of Airy functions are found.Comment: 15 pages, talk presented in Workshop `Nonlinear Physics IV: Theory and Experiment`, 22-30 June 2006, Gallipoli, Ital

Design and evaluation of a novel professional identity development program for pharmacy students

Professionalism, which is integral to the practice of pharmacy, is evolving to include a recognition of the importance of the development of professional identity. What is lacking, however is the presence of a framework for understanding the formation of student professional identity and the selection of suitable pedagogical approaches to facilitate such development. Educators are under increasing pressure to produce work-ready graduates, which involves the development of student professionalism. Current competency-based approaches focus on promoting student professional attitudes, values and behaviours. While these competencies are important to professional practice, they fail to adequately capture the complexity and richness of the professional role. A greater understanding of the mechanism of identity development, paired with pedagogies, which support identity formation, would better enable educators to adequately prepare students for professional practice. Professional identity is formed on two levels; the individual or psychological level and the collective level, also known as socialisation. The aim of this study was to develop a Professional Identity Program (PIP), designed to facilitate student professional identity formation, targeting the psychological development of the individual student. This study utilised the theoretical tenets of Self-Determination Theory (SDT), a psychological theory of human motivation and identity development, as a basis for the design of the program. SDT states that satisfaction of the three human basic psychological needs; competence, relatedness and autonomy, results in increased motivation (autonomy) and identity development. The PIP featured autonomy-supportive teaching in a longitudinal, early intervention, theory-based approach to professional development for pharmacy students. Methods Design: In line with the central tenets of SDT, the PIP was designed to support student competence, relatedness and autonomy, with a view to enhancing student motivation and eliciting identity development. Recognised pedagogical strategies for providing such support were employed throughout the 2 year program. Early intervention was a feature of this program, providing students with the opportunity to consider professionalism and professional identity development by participating in active discussions with practicing pharmacists and other students, in their first year of study. Emotional intelligence training was included in the program for its link to professional identity development. In addition approaches previously proven to enhance professional development such as reflective activity, role models and authentic practice-related activity were also incorporated into the program. Delivery: The PIP was integrated into the existing curricular structure, in each semester for the first two years of the BPharm. Sessions were delivered together with a practicing pharmacist, offering the students an opportunity to interact with the profession, in the absence of workplace exposure. Autonomy-supportive teaching techniques underpinned the delivery of the program, and a variety of teaching styles were employed to promote student participation and engagement. Evaluation: A previously validated professional identity measure, the McLeod Clarke Professional Identity Scale (MCPIS-9), was utilised as part of a mixed methods approach to the evaluation of the PIP. The Pharm-S, an instrument for measuring student motivation was adapted from an existing scale, modifying the context for pharmacy education. The Pharm-S was validated using recognised techniques and incorporated, alongside the MCPIS-9 and demographic questions to form the student survey. Students in two separate first year cohorts (2014 and 2015 intake) were surveyed at 0, 12 and 24 months. The 2014 cohort did not receive the PIP, whereas the 2015 cohort had the PIP integrated into their curriculum. The student survey scores were summarised as averages in the case of the MCPIS items, and a weighted scoring protocol, the Relative Autonomy Index (RAI) was used for the Pharm-S. To effectively explore inter and intra group differences, inferential statistical techniques, using non-parametric analysis, was undertaken. An additional survey, using likert-response, was also administered to the 2015 students for the purposes of evaluating the content and delivery of the PIP. Data from this survey were analysed using basic descriptive statistical techniques. Focus groups of first and fourth year students were also conducted to gain a more in-depth understanding of the student experience of professional development. Responses from the focus groups were audio recorded and transcribed. The written transcriptions were then analysed using an analytical framework identifying key concepts, which were subsequently organised into themes. Results The Pharm-S instrument proved to be suitable for use after successfully conducting face, content, test-retest, construct and convergent validation techniques. A positive correlation (r=0.64) between motivation scores and professional identity scores was also revealed. Analysis of the systematic monitoring of student motivation during the PIP, using the Pharm- S, showed a statistically significant increase in their motivation (autonomy) after 2 years participation in the program (U=421, Z=-2.5, p=0.012). Comparing student scores from those who received the PIP with student scores who did not receive the PIP, also revealed a statistically significant increase in motivation (autonomy) scores after two years in the program (Z=-2.3, p=0.020). Autonomy-supportive teaching has previously been reported to increase student autonomy through its student-centred focus1 and by increasing motivation to learn.²,³ Observed increases in motivation (autonomy) and a demonstrated link between Pharm-S and MCPIS-9 scores, provided evidence of professional identity formation when support is provided for student competence, relatedness and autonomy. This reflects the theoretical basis of SDT which states that the satisfaction of the three human basic psychological needs, lays a necessary foundation for identity development.⁴ The PIP was positively received by students with 100% stating that they gained a greater understanding of the importance of professionalism and 84% reporting that it improved their sense of professional identity (n=44, 88% response rate, M=18, F=26), mean age=20 yrs, SD=4.2). Student (first and fourth year) perceptions of their professional development revealed three major influencing factors; pharmacist-educators, curriculum and placement. Differences however were noted between groups, however, with the first years prioritising pharmacist educators and the fourth years, placement. Conclusion This study builds on and contributes to work in professional education by demonstrating the impact of an early intervention, theory-based, professional identity program. It is the first of its kind to apply the tenets of a psychological theory on motivation and to feature pedagogies that facilitate motivation and identity development in pharmacy students. Adopting autonomy-supportive teaching, a student-centred approach, increases their motivation and autonomy, this being linked with more effective patient-centred care and better patient health outcomes. References 1. Ten Cate TJ, Kusurkar RA, Williams GC. How self-determination theory can assist our understanding of the teaching and learning processes in medical education. AMEE guide No. 59. Med Teach. 2011;33(12):961-973. 2. Orsini C, Evans P, Jerez O. How to encourage intrinsic motivation in the clinical teaching environment?: a systematic review from the self-determination theory. J Educ Eval Health Prof. 2015;12(8). 3. Niemiec CP, Ryan RM. Autonomy, competence, and relatedness in the classroom: Applying self-determination theory to educational practice. Theory and Research in Education. 2009;7(2):133-144. 4. Luyckx K, Vansteenkiste M, Goossens L, Duriez B. Basic need satisfaction and identity formation: Bridging self-determination theory and process-oriented identity research. J Couns Psychol. 2009;56(2):276-288

Minkowski Functionals of Convergence Maps and the Lensing Figure of Merit

Minkowski functionals (MFs) quantify the topological properties of a given field probing its departure from Gaussianity. We investigate their use on lensing convergence maps in order to see whether they can provide further insights on the underlying cosmology with respect to the standard second-order statistics, i.e., cosmic shear tomography. To this end, we first present a method to match theoretical predictions with measured MFs taking care of the shape noise, imperfections in the map reconstruction, and inaccurate description of the nonlinearities in the matter power spectrum and bispectrum. We validate this method against simulated maps reconstructed from shear fields generated by the MICE simulation. We then perform a Fisher matrix analysis to forecast the accuracy on cosmological parameters from a joint MFs and shear tomography analysis. It turns out that MFs are indeed helpful to break the $\Omega_{\rm m}$--$\sigma_8$ degeneracy thus generating a sort of chain reaction leading to an overall increase of the Figure of Merit.Comment: 16 pages, 5 figures. Matches published version in PR