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1.  Establishing an academic laboratory: mentoring as a business model 
Molecular Biology of the Cell  2014;25(21):3251-3253.
It is a tremendous honor for my group and me to receive the recognition of the 2014 Women in Cell Biology Junior Award. I would like to take the opportunity of this essay to describe my scientific journey, discuss my philosophy about running a group, and propose what I think is a generalizable model to efficiently establish an academic laboratory. This essay is about my view on the critical components that go into establishing a highly functional academic laboratory during the current tough, competitive times.
doi:10.1091/mbc.E14-06-1079
PMCID: PMC4214767  PMID: 25360043
2.  ON THE MAKING OF A SYSTEM THEORY OF LIFE: PAUL A WEISS AND LUDWIG VON BERTALANFFY’S CONCEPTUAL CONNECTION 
The Quarterly review of biology  2007;82(4):349-373.
In this article, we review how two eminent Viennese system thinkers, Paul A Weiss and Ludwig von Bertalanffy, began to develop their own perspectives toward a system theory of life in the 1920s. Their work is especially rooted in experimental biology as performed at the Biologische Versuchsanstalt, as well as in philosophy, and they converge in basic concepts. We underline the conceptual connections of their thinking, among them the organism as an organized system, hierarchical organization, and primary activity. With their system thinking, both biologists shared a strong desire to overcome what they viewed as a “mechanistic” approach in biology. Their interpretations are relevant to the renaissance of system thinking in biology—“systems biology.” Unless otherwise noted, all translations are our own.
PMCID: PMC2874664  PMID: 18217527
organismic biology; theoretical biology; Biologische Versuchsanstalt; systems biology
3.  The introduction of medical humanities in the undergraduate curriculum of Greek medical schools: challenge and necessity 
Hippokratia  2010;14(4):241-243.
Background and Aim: Medical humanities is a multidisciplinary field, consisting of humanities (theory of literature and arts, philosophy, ethics, history and theology), social sciences (anthropology, psychology and sociology) and arts (literature, theater, cinema, music and visual arts), integrated in the undergraduate curriculum of Medical schools. The aim of the present study is to discuss medical humanities and support the necessity of introduction of a medical humanities course in the curriculum of Greek medical schools.
Materials, Methods and Results: Through the relevant Pub-Med search as well as taking into account various curricula of medical schools, it is evident that medical education today is characterized by acquisition of knowledge and skills and development of medical values and attitudes. Clinical observation with the recognition of key data and patterns in the collected information, is crucial in the final medical decision, i.e. in the complex process, through which doctors accumulate data, reach conclusions and decide on therapy. All sciences included in medical humanities are important for the high quality education of future doctors. The practice of Medicine is in large an image-related science. The history of anatomy and art are closely related, already from the Renaissance time. Studies have shown that attendance of courses on art critics improves the observational skills of medical students. Literature is the source of information about the nature and source of human emotions and behavior and of narratives of illness, and increases imagination. Philosophy aids in the development of analytical and synthetical thinking. Teaching of history of medicine develops humility and aids in avoiding the repetition of mistakes of the past, and quite often raises research and therapeutic skepticism. The comprehension of medical ethics and professional deontology guides the patient-doctor relationship, as well as the relations between physicians and their colleagues. The Medical Humanities course, which is already integrated in the undergraduate curriculum of many medical schools of Europe, USA and Australia, includes lectures by experts and students presentations on the above-mentioned areas and could be offered, for a semester, during the first years.
Conclusion: The aim of Medical Humanities course is the development of imagination and interpretation of data through analytical complex procedures, the development of skills of close observation and careful interpretation of the patient "language" and the enhancement of empathy for the patients, as well as the development of the physician-patient relationship and finally the conceptualization/construction of personal and professional values.
PMCID: PMC3031316  PMID: 21311630
medical humanities; Greece; medical school; review
4.  Right Language to Release the River of Health in the Medical Industry 
Performance artist Laurie Anderson appropriated an idea from beat writer William Burroughs a few years back. Language, Anderson sings, is a virus.1 The words we choose lock in ideas and discharge reverberations. They subtly evoke personal, professional, and societal power relationships. Language is a virus.
By extension, changes of language can shift power relations. The removal of a conquest name of a former US president from the highest point in the northern part of the western hemisphere is a case in point. US President Barack Obama re-anointed Mt McKinley as Mt Denali, the name used by the indigenous people whose descendants still live in its presence.2 The act replaced a European surname linked to cultural suppression and colonization with one that honors the first human inhabitants.
The renaissance of indigenous medical practices is effecting a similar renaming of what many view to be the high point in the development of medicine. “Traditional medicine” has for decades been misused to describe biomedical and industrial practices that are less than a century old. Better to qualify this medicine with “conventional” or “bio-.” Let “traditional medicine” indicate practices that carry the weight of history. These choices move toward right language.
doi:10.7453/gahmj.2015.122
PMCID: PMC4653598  PMID: 26665015
Language; health; healthcare system
5.  The origins of Western mind–body exercise methods 
Physical Therapy Reviews  2016;20(5-6):315-324.
Background: Over recent decades, mind–body exercise methods have gained international popularity and importance in the management of musculoskeletal disorders.
Objectives: The scope of this paper was to investigate: the origins of Western mind–body methods, their philosophies, exercises, and relationship with mainstream healthcare over the last two centuries.
Major findings: Within a few decades of the turn of the 20th century, a cluster of mind–body exercise methods emerged from at least six pioneering founders: Checkley, Müller, Alexander, Randell, Pilates, and Morris. Each was based upon a similar exercise philosophy and similar functional movement-harmonizing exercises. This renaissance of independent mind–body schools occurred in parallel with the demise of the 18th and 19th century gymnasium Physical Culture movement and the concurrent emergence of bodybuilding and strength training. Even though mostly forgotten today, Western mind–body exercise methods enjoyed celebrated success during the first half of the 20th century, were hailed by medical and allied health practitioners and practiced by millions from society’s elite to deprived minorities.
Conclusions: Rediscovering the Western mind–body exercise movement is hoped to facilitate official healthcare establishment recognition of this kind of training as an integral entity. This may widen research opportunities and consolidate approaches toward: optimal musculoskeletal rehabilitation and injury prevention, promotion of a healthy active lifestyle environment in the modern world, and enhancement of the natural pain-free human athletic look, feel, and performance.
doi:10.1080/10833196.2015.1125587
PMCID: PMC5022134  PMID: 27695277
Functional exercises; Harmonious movements; Physical therapy; Preventative medicine; Active lifestyle; History
6.  Oskar Is Targeted for Degradation by the Sequential Action of Par-1, GSK-3, and the SCF-Slimb Ubiquitin Ligase 
Developmental Cell  2013;26(3):303-314.
Summary
Translation of oskar messenger RNA (mRNA) is activated at the posterior of the Drosophila oocyte, producing Long Oskar, which anchors the RNA, and Short Oskar, which nucleates the pole plasm, containing the posterior and germline determinants. Here, we show that Oskar is phosphorylated by Par-1 and GSK-3/Shaggy to create a phosphodegron that recruits the SCF-Slimb ubiquitin ligase, which targets Short Oskar for degradation. Phosphorylation site mutations cause Oskar overaccumulation, leading to an increase in pole cell number and embryonic patterning defects. Furthermore, the nonphosphorylatable mutant produces bicaudal embryos when oskar mRNA is mislocalized. Thus, the Par-1/GSK-3/Slimb pathway plays important roles in limiting the amount of pole plasm posteriorly and in degrading any mislocalized Oskar that results from leaky translational repression. These results reveal that Par-1 controls the timing of pole plasm assembly by promoting the localization of oskar mRNA but inhibiting the accumulation of Short Oskar protein.
Graphical Abstract
Highlights
•Par-1 phosphorylates Short Osk to prime it for GSK-3 phosphorylation•This marks Short Osk for degradation through recruitment of the SCFSlimb complex•Par-1 promotes oskar messenger RNA localization but inhibits short Osk accumulation•This removes mislocalized Osk and controls the timing of pole plasm assembly
Drosophila axis formation depends on the tight localization of Oskar to the oocyte posterior by messenger RNA localization and translational repression. Morais-de-Sá et al. describe another essential control mechanism in which Par-1, GSK-3, and an SCF ubiquitin ligase induce Oskar degradation to prevent ectopic or excess Oskar from disrupting patterning.
doi:10.1016/j.devcel.2013.06.011
PMCID: PMC3744808  PMID: 23948254
7.  A passion for the science of the human genome 
Molecular Biology of the Cell  2012;23(21):4154-4156.
The complete sequencing of the human genome introduced a new knowledge base for decoding information structured in DNA sequence variation. My research is predicated on the supposition that the genome is the most sophisticated knowledge system known, as evidenced by the exquisite information it encodes on biochemical pathways and molecular processes underlying the biology of health and disease. Also, as a living legacy of human origins, migrations, adaptations, and identity, the genome communicates through the complexity of sequence variation expressed in population diversity. As a biomedical research scientist and academician, a question I am often asked is: “How is it that a black woman like you went to the University of Michigan for a PhD in Human Genetics?” As the ASCB 2012 E. E. Just Lecturer, I am honored and privileged to respond to this question in this essay on the science of the human genome and my career perspectives.
doi:10.1091/mbc.E12-05-0342
PMCID: PMC3484090  PMID: 23112225
8.  Psychosomatic medicine and the philosophy of life 
Basing ourselves on the writings of Hans Jonas, we offer to psychosomatic medicine a philosophy of life that surmounts the mind-body dualism which has plagued Western thought since the origins of modern science in seventeenth century Europe. Any present-day account of reality must draw upon everything we know about the living and the non-living. Since we are living beings ourselves, we know what it means to be alive from our own first-hand experience. Therefore, our philosophy of life, in addition to starting with what empirical science tells us about inorganic and organic reality, must also begin from our own direct experience of life in ourselves and in others; it can then show how the two meet in the living being. Since life is ultimately one reality, our theory must reintegrate psyche with soma such that no component of the whole is short-changed, neither the objective nor the subjective. In this essay, we lay out the foundational components of such a theory by clarifying the defining features of living beings as polarities. We describe three such polarities:
1) Being vs. non-being: Always threatened by non-being, the organism must constantly re-assert its being through its own activity.
2) World-relatedness vs. self-enclosure: Living beings are both enclosed with themselves, defined by the boundaries that separate them from their environment, while they are also ceaselessly reaching out to their environment and engaging in transactions with it.
3) Dependence vs. independence: Living beings are both dependent on the material components that constitute them at any given moment and independent of any particular groupings of these components over time.
We then discuss important features of the polarities of life: Metabolism; organic structure; enclosure by a semi-permeable membrane; distinction between "self" and "other"; autonomy; neediness; teleology; sensitivity; values. Moral needs and values already arise at the most basic levels of life, even if only human beings can recognize such values as moral requirements and develop responses to them.
doi:10.1186/1747-5341-5-2
PMCID: PMC2823620  PMID: 20089202
9.  Brain ‘imaging’ in the Renaissance 
During the Renaissance, a period of ‘rebirth’ for humanities and science, new knowledge and speculation began to emerge about the function of the human body, replacing ancient religious and philosophical dogma. The brain must have been a fascinating mystery to a Renaissance artist, but some speculation existed at that time on the function of its parts. Here we show how revived interest in anatomy and life sciences may have influenced the figurative work of Italian and Flemish masters, such as Rafael, Michelangelo and David. We present a historical perspective on the artists and the period in which they lived, their fascination for human anatomy and its symbolic use in their art.
Prior to the 16th century, knowledge of the brain was limited and influenced in a dogmatic way by the teachings of Galen1 who, as we now know, conducted his anatomical studies not on humans but on animals.2 Nemesus, Bishop of Emesa, in around the year 400 was one of the first to attribute mental faculties to the brain, specifically to the ventricles. He identified two anterior (lateral) ventricles, to which he assigned perception, a middle ventricle responsible for cognition and a posterior ventricle for memory.2,3 After a long period of stasis in the Middle Ages, Renaissance scholars realized the importance of making direct observations on dissected cadavers. Between 1504 and 1507, Leonardo da Vinci conducted experiments to reveal the anatomy of the ventricular system in the brain. He injected hot wax through a tube thrust into the ventricular cavities of an ox and then scraped the overlying brain off, thus obtaining, in a simple but ingenious way, an accurate cast of the ventricles.2,4 Leonardo shared the belief promoted by scholarly Christians that the ventricles were the abode of rational soul.
We have several examples of hidden symbolism in Renaissance paintings, but the influence of phrenology and this rudimentary knowledge of neuroanatomy on artists of that period is under-recognized. In the absence of documentary or scientific evidence as to the real intentions of these painters, the notion of such commixture of sacred and profane remains speculative and probably controversial, but at the same time fascinating and provocative. Here we present three examples of Renaissance masterpieces where such symbolism may have been used, although probably many more exist. Conducting an artistic, philosophical and anatomical analysis of the paintings can be an intriguing exercise, but the interpretation will inevitably be conjectural.
PMCID: PMC2121627  PMID: 18065703
10.  An Oskar-Dependent Positive Feedback Loop Maintains the Polarity of the Drosophila Oocyte 
Current Biology  2007;17(4):353-359.
Summary
The localization of oskar mRNA to the posterior of the Drosophila oocyte defines the site of assembly of the pole plasm, which contains the abdominal and germline determinants [1–3]. oskar mRNA localization requires the polarization of the microtubule cytoskeleton, which depends on the recruitment of PAR-1 to the posterior cortex in response to a signal from the follicle cells, where it induces an enrichment of microtubule plus ends [4–7]. Here, we show that overexpressed oskar mRNA localizes to the middle of the oocyte, as well as the posterior. This ectopic localization depends on the premature translation of Oskar protein, which recruits PAR-1 and microtubule-plus-end markers to the oocyte center instead of the posterior pole, indicating that Oskar regulates the polarity of the cytoskeleton. Oskar also plays a role in the normal polarization of the oocyte; mutants that disrupt oskar mRNA localization or translation strongly reduce the posterior recruitment of microtubule plus ends. Thus, oskar mRNA localization is required to stabilize and amplify microtubule polarity, generating a positive feedback loop in which Oskar recruits PAR-1 to the posterior to increase the microtubule cytoskeleton's polarization, which in turn directs the localization of more oskar mRNA.
doi:10.1016/j.cub.2006.12.044
PMCID: PMC1885951  PMID: 17275299
CELLBIO; RNA; DEVBIO
11.  Barentsz is essential for the posterior localization of oskar mRNA and colocalizes with it to the posterior pole 
The Journal of Cell Biology  2001;154(3):511-524.
The localization of Oskar at the posterior pole of the Drosophila oocyte induces the assembly of the pole plasm and therefore defines where the abdomen and germ cells form in the embryo. This localization is achieved by the targeting of oskar mRNA to the posterior and the localized activation of its translation. oskar mRNA seems likely to be actively transported along microtubules, since its localization requires both an intact microtubule cytoskeleton and the plus end–directed motor kinesin I, but nothing is known about how the RNA is coupled to the motor. Here, we describe barentsz, a novel gene required for the localization of oskar mRNA. In contrast to all other mutations that disrupt this process, barentsz-null mutants completely block the posterior localization of oskar mRNA without affecting bicoid and gurken mRNA localization, the organization of the microtubules, or subsequent steps in pole plasm assembly. Surprisingly, most mutant embryos still form an abdomen, indicating that oskar mRNA localization is partially redundant with the translational control. Barentsz protein colocalizes to the posterior with oskar mRNA, and this localization is oskar mRNA dependent. Thus, Barentsz is essential for the posterior localization of oskar mRNA and behaves as a specific component of the oskar RNA transport complex.
doi:10.1083/jcb.200105056
PMCID: PMC2196428  PMID: 11481346
Drosophila; axis formation; pole plasm; microtubules; RNA transport
12.  Cup is an eIF4E binding protein required for both the translational repression of oskar and the recruitment of Barentsz 
The Journal of Cell Biology  2003;163(6):1197-1204.
In Drosophila oocytes, precise localization of the posterior determinant, Oskar, is required for posterior patterning. This precision is accomplished by a localization-dependent translational control mechanism that ensures translation of only correctly localized oskar transcripts. Although progress has been made in identifying localization factors and translational repressors of oskar, none of the known components of the oskar complex is required for both processes. Here, we report the identification of Cup as a novel component of the oskar RNP complex. cup is required for oskar mRNA localization and is necessary to recruit the plus end–directed microtubule transport factor Barentsz to the complex. Surprisingly, Cup is also required to repress the translation of oskar. Furthermore, eukaryotic initiation factor 4E (eIF4E) is localized within the oocyte in a cup-dependent manner and binds directly to Cup in vitro. Thus, Cup is a translational repressor of oskar that is required to assemble the oskar mRNA localization machinery. We propose that Cup coordinates localization with translation.
doi:10.1083/jcb.200309088
PMCID: PMC2173729  PMID: 14691132
oskar mRNA; oogenesis; Drosophila; Barentsz; eIF4E binding protein
13.  Dynein Associates with oskar mRNPs and Is Required For Their Efficient Net Plus-End Localization in Drosophila Oocytes 
PLoS ONE  2013;8(11):e80605.
In order for eukaryotic cells to function properly, they must establish polarity. The Drosophila oocyte uses mRNA localization to establish polarity and hence provides a genetically tractable model in which to study this process. The spatial restriction of oskar mRNA and its subsequent protein product is necessary for embryonic patterning. The localization of oskar mRNA requires microtubules and microtubule-based motor proteins. Null mutants in Kinesin heavy chain (Khc), the motor subunit of the plus end-directed Kinesin-1, result in oskar mRNA delocalization. Although the majority of oskar particles are non-motile in khc nulls, a small fraction of particles display active motility. Thus, a motor other than Kinesin-1 could conceivably also participate in oskar mRNA localization. Here we show that Dynein heavy chain (Dhc), the motor subunit of the minus end-directed Dynein complex, extensively co-localizes with Khc and oskar mRNA. In addition, immunoprecipitation of the Dynein complex specifically co-precipitated oskar mRNA and Khc. Lastly, germline-specific depletion of Dhc resulted in oskar mRNA and Khc delocalization. Our results therefore suggest that efficient posterior localization of oskar mRNA requires the concerted activities of both Dynein and Kinesin-1.
doi:10.1371/journal.pone.0080605
PMCID: PMC3823658  PMID: 24244700
14.  Highlights from the 11th ISCB Student Council Symposium 2015 
BMC Bioinformatics  2016;17(Suppl 3):95.
Table of contents
A1 Highlights from the eleventh ISCB Student Council Symposium 2015
Katie Wilkins, Mehedi Hassan, Margherita Francescatto, Jakob Jespersen, R. Gonzalo Parra, Bart Cuypers, Dan DeBlasio, Alexander Junge, Anupama Jigisha, Farzana Rahman
O1 Prioritizing a drug’s targets using both gene expression and structural similarity
Griet Laenen, Sander Willems, Lieven Thorrez, Yves Moreau
O2 Organism specific protein-RNA recognition: A computational analysis of protein-RNA complex structures from different organisms
Nagarajan Raju, Sonia Pankaj Chothani, C. Ramakrishnan, Masakazu Sekijima; M. Michael Gromiha
O3 Detection of Heterogeneity in Single Particle Tracking Trajectories
Paddy J Slator, Nigel J Burroughs
O4 3D-NOME: 3D NucleOme Multiscale Engine for data-driven modeling of three-dimensional genome architecture
Przemysław Szałaj, Zhonghui Tang, Paul Michalski, Oskar Luo, Xingwang Li, Yijun Ruan, Dariusz Plewczynski
O5 A novel feature selection method to extract multiple adjacent solutions for viral genomic sequences classification
Giulia Fiscon, Emanuel Weitschek, Massimo Ciccozzi, Paola Bertolazzi, Giovanni Felici
O6 A Systems Biology Compendium for Leishmania donovani
Bart Cuypers, Pieter Meysman, Manu Vanaerschot, Maya Berg, Hideo Imamura, Jean-Claude Dujardin, Kris Laukens
O7 Unravelling signal coordination from large scale phosphorylation kinetic data
Westa Domanova, James R. Krycer, Rima Chaudhuri, Pengyi Yang, Fatemeh Vafaee, Daniel J. Fazakerley, Sean J. Humphrey, David E. James, Zdenka Kuncic
doi:10.1186/s12859-016-0901-4
PMCID: PMC4895264  PMID: 26986007
15.  Analysis of the ‘reformpool’-activity in Austria: is the challenge met? 
Aim
The purpose of our study is to analyse the activities initiated by the foundation of the reformpools on the regional level. We wanted to see not only what projects have emerged from these funds, but also how the incentives of this special way of funding influence the activity and what overall impact can be expected on health services delivery in the future.
Context
In Austria, all expenses in the outpatient sector are borne by the statutory health insurance. But in the inpatient sector, SHI just co-finances about 45% of all costs incurred by patients, with the rest contributed by the federal, regional and municipal level. This, however, leads to a number of problems in today's epidemiological situation with patients in need of many different interventions in the course of their chronic disease.
Originally with the aim of finding solutions to these interface problems between inpatient and outpatient care, the healthcare reform 2005 instated the instrument of the reformpool. The reformpool unites funds from social health insurance and regions to finance projects that develop new ways of health services delivery across the sectors. In the course of recent reforms, it became explicitly possible to sponsor projects of integrated care, which had de facto already been the case before.
Theory
The reform pool has various disincentives or wrong incentives compared to e.g. the German ‘Anschubfinanzierung’ for IC-contracts, which was probably a role-model for the Austrian reformpool, because of the underlying differences in the healthcare system and the distinct differences in the regulation. For example, the ‘Anschubfinanzierung’ in Germany withdraws money from the available funds for contract physicians to finance IC-projects, whereas in Austria, their fees are fixed. So in Austria, there is no incentive to retrieve money by participating in such projects. For the stakeholders supplying the pool, mainly the sickness funds and the regions, many projects inflict additional costs on the one or on the other in the future. So as both parties have to agree on projects, there is a strong basic disincentive to grant funds in the present. If a project is in both their interest because it is reducing costs, the care providers might not be interested to participate, as this would diminish their revenues in the future. What is more, the federal control over the (region-based) funds and projects is poor, which might lead to duplication of efforts and missing scale-efficiency in some regions.
Methods and data
For our analysis, we conducted a survey with a standardised questionnaire sent to the management of the regional health funds, which are responsible for the reformpool funds. The questionnaire was checked by experts of the federal association of social security institutions. We also conducted an on-site visit of the reformpool-manager, a programme which can be used to evaluate the reformpool-projects. In addition, we used all available evaluation reports of projects to assess the situation of evaluation of the projects. Furthermore, we used financial data from the regional health funds, the federal association of social security institutions, from the ministry of health and the regional health funds to assess the usage of the reformpool.
(Preliminary) Results
The qualitative results are mixed. Some projects are promising with regard to improvements of the current situation and are well evaluated. Many projects neglect the requirement of the reformpool to be such as to yield a monetary benefit for the system but only focus on improving service delivery. Some evaluations are not well operationalised and thus, arguments why these projects should be transformed to ordinarily financed services will be lacking. The reformpool activity set on very slowly, with only one project already started in 2005, the first possible year. In 2007 we see the highest number (23) of new projects granted and the highest monetary volume, €11 Mio total for 21 of them 1, with activity subsiding in 2008 (6 projects with a volume of € 2.5 Mio total for 5 of them 1) and most certainly in 2009 (with diminishing tax revenues and health insurance contributions) with only one project granted in the first quarter of the year. Of all funds (theoretically) available, only about 16% have been put to use in a reformpool project per year, with high variation (e.g. in the region of Styria over 30%, in Tyrol only 1.5%).
(Preliminary) Conclusions
From our study we can tell that the instrument of reformpool was not devised well concerning its incentive structure, and the interest to conduct such projects is diminishing. Stricter control of the requirements by the federal level, more pronounced requirements, a dedication of the funds to projects instead of a virtual budget and more cooperation between regions could improve the effectiveness of the instrument. Conflicts of interest: The project was funded by the federal association of social security institutions. All authors are researchers at the IHS and hold no commercial interests in the subject. Additional information: Founded by the economist Oskar Morgenstern and the sociologist Paul Lazarsfeld, the IHS (Institute for Advanced Studies) is a non-profit post-graduate teaching and research facility in the fields of economics, sociology and politology, and one of the two Austrian institutes preparing the official economic forecast for Austria. For more than a decade, it has been one of the major research facilities in the fields of health economics and health policy in Austria.
PMCID: PMC2807071
evidence-based guidelines; quality of care
16.  Genome-Wide Identification of Genes Required for Fitness of Group A Streptococcus in Human Blood 
Infection and Immunity  2013;81(3):862-875.
The group A streptococcus (GAS) is a strict human pathogen responsible for a wide spectrum of diseases. Although GAS genome sequences are available, functional genomic analyses have been limited. We developed a mariner-based transposon, osKaR, designed to perform Transposon-Site Hybridization (TraSH) in GAS and successfully tested its use in several invasive serotypes. A complex osKaR mutant library in M1T1 GAS strain 5448 was subjected to negative selection in human blood to identify genes important for GAS fitness in this clinically relevant environment. Mutants underrepresented after growth in blood (output pool) compared to growth in rich media (input pool) were identified using DNA microarray hybridization of transposon-specific tags en masse. Using blood from three different donors, we identified 81 genes that met our criteria for reduced fitness in blood from at least two individuals. Genes known to play a role in survival of GAS in blood were found, including those encoding the virulence regulator Mga (mga), the peroxide response regulator PerR (perR), and the RofA-like regulator Ralp-3 (ralp3). We also identified genes previously reported for their contribution to sepsis in other pathogens, such as de novo nucleotide synthesis (purD, purA, pyrB, carA, carB, guaB), sugar metabolism (scrB, fruA), zinc uptake (adcC), and transcriptional regulation (cpsY). To validate our findings, independent mutants with mutations in 10 different genes identified in our screen were confirmed to be defective for survival in blood bactericidal assays. Overall, this work represents the first use of TraSH in GAS to identify potential virulence genes.
doi:10.1128/IAI.00837-12
PMCID: PMC3584890  PMID: 23297387
17.  From the “metaphysics of the individual” to the critique of society: on the practical significance of Michel Henry’s phenomenology of life 
Continental Philosophy Review  2012;45:339-361.
This essay explores the practical significance of Michel Henry’s “material phenomenology.” Commencing with an exposition of his most basic philosophical intuition, i.e., his insight that transcendental affectivity is the primordial mode of revelation of our selfhood, the essay then brings to light how this intuition also establishes our relation to both the world and others. Animated by a radical form of the phenomenological reduction, Henry’s material phenomenology brackets the exterior world in a bid to reach the concrete interior transcendental experience at the base of all exteriority. The essay argues that this “counter reduction,” designed as a practical orientation to the world, suspends all traditional parameters of onto(theo)logical individuation in order to rethink subjectivity in terms of its transcendental corporeality, i.e., in terms of the invisible display of “affective flesh.” The development of this “metaphysics of the individual” anchors his “practical philosophy” as he developed it—under shifting accents—throughout his oeuvre. In particular, the essay brings into focus Henry’s reflections on modernity, the industry of mass culture and their “barbaric” movements. The essay briefly puts these cultural and political areas of Henry’s of thinking into contact with his late “theological turn,” i.e., his Christological account of Life and the (inter)subjective self-realization to which it gives rise.
doi:10.1007/s11007-012-9226-9
PMCID: PMC4837930  PMID: 27182196
Material phenomenology; Michel Henry; Theological turn; Transcendendal corporeality
18.  Klar ensures thermal robustness of oskar localization by restraining RNP motility 
The Journal of Cell Biology  2014;206(2):199-215.
When temperature fluctuation threatens the fidelity of Drosophila oogenesis, Klar restrains posterior-ward translocation of oskar mRNA, thereby adapting the rate of oskar delivery to the capacity of the anchoring machinery.
Communication usually applies feedback loop–based filters and amplifiers to ensure undistorted delivery of messages. Such an amplifier acts during Drosophila melanogaster midoogenesis, when oskar messenger ribonucleic acid (mRNA) anchoring depends on its own locally translated protein product. We find that the motor regulator Klar β mediates a gain-control process that prevents saturation-based distortions in this positive feedback loop. We demonstrate that, like oskar mRNA, Klar β localizes to the posterior pole of oocytes in a kinesin-1–dependent manner. By live imaging and semiquantitative fluorescent in situ hybridization, we show that Klar β restrains oskar ribonucleoprotein motility and decreases the posterior-ward translocation of oskar mRNA, thereby adapting the rate of oskar delivery to the output of the anchoring machinery. This negative regulatory effect of Klar is particularly important for overriding temperature-induced changes in motility. We conclude that by preventing defects in oskar anchoring, this mechanism contributes to the developmental robustness of a poikilothermic organism living in a variable temperature environment.
doi:10.1083/jcb.201310010
PMCID: PMC4107779  PMID: 25049271
19.  Community effects in regulation of translation 
eLife  null;5:e10965.
Certain forms of translational regulation, and translation itself, rely on long-range interactions between proteins bound to the different ends of mRNAs. A widespread assumption is that such interactions occur only in cis, between the two ends of a single transcript. However, certain translational regulatory defects of the Drosophila oskar (osk) mRNA can be rescued in trans. We proposed that inter-transcript interactions, promoted by assembly of the mRNAs in particles, allow regulatory elements to act in trans. Here we confirm predictions of that model and show that disruption of PTB-dependent particle assembly inhibits rescue in trans. Communication between transcripts is not limited to different osk mRNAs, as regulation imposed by cis-acting elements embedded in the osk mRNA spreads to gurken mRNA. We conclude that community effects exist in translational regulation.
DOI: http://dx.doi.org/10.7554/eLife.10965.001
eLife digest
Genes encode the instructions needed to make proteins and other molecules. To make a protein, the DNA within a gene is copied to produce molecules of messenger ribonucleic acid (mRNA) that are then used as templates to build proteins via a process called translation. This process – which involves protein machines called ribosomes binding to the start of the mRNA – is tightly regulated to control the amounts of particular proteins in cells. For example, in fruit fly ovaries, a protein called Bruno both represses and activates the translation of a gene known as oskar. To achieve this, Bruno binds to regions near the end of the oskar RNA known as Bruno response elements.
It is not clear how Bruno acts to control translation. However, because ribosomes begin translation near the start of the mRNA, while Bruno is bound to regions near the end of the mRNA, there must be long-range interactions between the two ends of the mRNA. It is generally assumed that such long-range interactions only occur between proteins that are bound to the same mRNA molecule. However, in 2010, researchers observed that Bruno response elements within one oskar mRNA could influence the translation of other oskar mRNAs. This is known as “regulation in trans”. Here, Macdonald et al. – including some of the researchers from the earlier work – investigated this observation in more detail in fruit flies.
In cells, multiple mRNA molecules and their associated proteins can assemble into particles. Macdonald et al. proposed that the close proximity of many mRNA molecules in these particles could allow trans regulation to take place. Indeed, the experiments found that blocking the assembly of oskar mRNA into particles inhibited trans regulation as expected. Macdonald et al. also asked if trans regulation can occur between mRNAs that encode different proteins. The experiments show that oskar mRNA could block the translation of an mRNA produced by the gurken gene, even when oskar mRNA was not being translated. More work is needed to find out how widely trans regulation is used to control translation.
DOI: http://dx.doi.org/10.7554/eLife.10965.002
doi:10.7554/eLife.10965
PMCID: PMC4846370  PMID: 27104756
translation; translational regulation; regulation in trans; RNP; D. melanogaster
20.  International Institute for Collaborative Cell Biology and Biochemistry—History and Memoirs from an International Network for Biological Sciences 
CBE Life Sciences Education  2013;12(3):339-344.
Memoirs by the 2012 recipient of the Bruce Alberts Award for Excellence in Science Education from the American Society for Cell Biology about the establishment of the International Institute for Collaborative Cell Biology and Biochemistry, which wants to inspire a new era of international scientific cooperation by exposing scientists to diverse learning experiences.
I was invited to write this essay on the occasion of my selection as the recipient of the 2012 Bruce Alberts Award for Excellence in Science Education from the American Society for Cell Biology (ASCB). Receiving this award is an enormous honor. When I read the email announcement for the first time, it was more than a surprise to me, it was unbelievable. I joined ASCB in 1996, when I presented a poster and received a travel award. Since then, I have attended almost every ASCB meeting. I will try to use this essay to share with readers one of the best experiences in my life. Because this is an essay, I take the liberty of mixing some of my thoughts with data in a way that it not usual in scientific writing. I hope that this sacrifice of the format will achieve the goal of conveying what I have learned over the past 20 yr, during which time a group of colleagues and friends created a nexus of knowledge and wisdom. We have worked together to build a network capable of sharing and inspiring science all over the world.
doi:10.1187/cbe.13-06-0108
PMCID: PMC3763000  PMID: 24006381
21.  Debi Ghate and Richard E. Ralston: Why businessmen need philosophy: the capitalist’s guide to the ideas behind Ayn Rand’s Atlas Shrugged 
Poiesis & Praxis  2012;8:197-201.
The essays in this book are meant to serve as an introduction to those ideas of Ayn Rand, which are of particular relevance to business people. Rand was known as a spirited defender of the laissez-faire free enterprise system. It is less commonly known that Rand was also deeply committed to the centrality of the enterprise of philosophy for both public and private life. The essays in this book try to bridge the gap between these two aspects of Rand’s thought. The results of the review of the book are mostly positive. The review attempts to separate the different themes in the book such as the importance of philosophy in general, the importance of philosophy for business, the philosophical defense of the free enterprise system and then to evaluate the evidence and arguments presented by the essayists for each claim.
doi:10.1007/s10202-012-0106-5
PMCID: PMC3368105
22.  Are animal models predictive for humans? 
It is one of the central aims of the philosophy of science to elucidate the meanings of scientific terms and also to think critically about their application. The focus of this essay is the scientific term predict and whether there is credible evidence that animal models, especially in toxicology and pathophysiology, can be used to predict human outcomes. Whether animals can be used to predict human response to drugs and other chemicals is apparently a contentious issue. However, when one empirically analyzes animal models using scientific tools they fall far short of being able to predict human responses. This is not surprising considering what we have learned from fields such evolutionary and developmental biology, gene regulation and expression, epigenetics, complexity theory, and comparative genomics.
doi:10.1186/1747-5341-4-2
PMCID: PMC2642860  PMID: 19146696
23.  Retrospective diagnosis of a famous historical figure: ontological, epistemic, and ethical considerations 
The aim of this essay is to elaborate philosophical and ethical underpinnings of posthumous diagnosis of famous historical figures based on literary and artistic products, or commonly called retrospective diagnosis. It discusses ontological and epistemic challenges raised in the humanities and social sciences, and attempts to systematically reply to their criticisms from the viewpoint of clinical medicine, philosophy of medicine, particularly the ontology of disease and the epistemology of diagnosis, and medical ethics. The ontological challenge focuses on the doubt about the persistence of a disease over historical time, whereas the epistemic challenge disputes the inaccessibility of scientific verification of a diagnosis in the past. I argue that the critics are in error in conflating the taxonomy of disease (nosology) and the act of diagnosing a patient. Medical diagnosis is fundamentally a hypothesis-construction and an explanatory device that can be generated under various degrees of uncertainty and limited amount of information. It is not an apodictic judgment (true or false) as the critics presuppose, but a probabilistic (Bayesian) judgment with varying degrees of plausibility under uncertainty. In order to avoid this confusion, I propose that retrospective diagnosis of a historical figure be syndromic without identifying underlying disease, unless there is justifiable reason for such specification. Moreover it should be evaluated not only from the viewpoint of medical science but also in a larger context of the scholarship of the humanities and social sciences by its overall plausibility and consistency. On the other hand, I will endorse their concerns regarding the ethics and professionalism of retrospective diagnosis, and call for the need for situating such a diagnosis in an interdisciplinary scope and the context of the scholarship of the historical figure. I will then enumerate several important caveats for interdisciplinary retrospective diagnosis using an example of the retrospective diagnosis of Socrates for his life-long intermittent neurologic symptoms. Finally, I will situate the present argument in a larger context of the major debate among the historians of medicine and paleopathologists, and discuss the similarities and differences.
doi:10.1186/1747-5341-9-10
PMCID: PMC4049481  PMID: 24884777
Retrospective diagnosis; Philosophy of medicine; History of medicine; Medical ethics; Ontology of disease; Epistemology in medicine; Pathography; Socrates; Plato; Frédéric Chopin
24.  Global mental health and neuroethics 
BMC Medicine  2015;13:44.
Background
Global mental health is a relatively new field that has focused on disparities in mental health services across different settings, and on innovative ways to provide feasible, acceptable, and effective services in poorly-resourced settings. Neuroethics, too, is a relatively new field, lying at the intersection of bioethics and neuroscience; it has studied the implications of neuroscientific findings for age-old questions in philosophy, as well as questions about the ethics of novel neuroscientific methods and interventions.
Discussion
In this essay, we address a number of issues that lie at the intersection of these two fields: an emphasis on a naturalist and empirical position, a concern with both disease and wellness, the importance of human rights in neuropsychiatric care, and the value of social inclusion and patient empowerment.
Summary
These different disciplines share a number of perspectives, and future dialogue between the two should be encouraged.
doi:10.1186/s12916-015-0274-y
PMCID: PMC4349616  PMID: 25858581
Global mental health; Neuroethics; Psychiatry; Neuroscience
25.  The inflammasome: in memory of Dr. Jurg Tschopp 
A decade ago, Jurg Tschopp introduced the concept of the inflammasome. This exciting discovery of a macromolecular complex that senses ‘danger' and initiates the inflammatory response contributed to a renaissance in the fields of innate immunity and cell death. Jurg led the biochemical characterization of the inflammasome complex and demonstrated that spontaneous hyperactivation of this interleukin (IL)-1β processing machinery is the molecular basis of a spectrum of hereditary periodic fever syndromes, caused by mutated forms of the inflammasome scaffolding receptor, NLRP3. The identification of the underlying mechanism in these disorders has led to their now successful therapy, with the use of the IL-1 receptor antagonist in the clinic. Jurg's pioneering work has subsequently defined a number of inflammasome agonists ranging from microbial molecules expressed during infection, to triggers of sterile inflammation, most notably gout-associated uric acid crystals, asbestos, silica and nanoparticles. More recently, Jurg introduced the critical new concept of the metabolic inflammasome, which senses metabolic stress and contributes to the onset of the metabolic syndrome associated with obesity and type 2 diabetes. Jurg was an outstanding and skillful biochemist, an elegant and rigorous researcher often far ahead of his peers. He was a truly amiable person, fair, generous and inspiring, and will be most remembered for his infectious enthusiasm. We write this review article on the inflammasome in his honor and dedicate it to his memory.
doi:10.1038/cdd.2011.159
PMCID: PMC3252823  PMID: 22075986
inflammasome; sterile inflammation; metabolism

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