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1.  Have we entered the brown adipose tissue renaissance? 
Summary
In the 1970s and 1980s, it was observed that rodents could offset excess calories ingested when they were fed a human-like `cafeteria diet'. Although it was erroneously concluded that this so-called diet-induced thermogenesis was because of brown adipose tissue (BAT), it led to efforts to test whether variations in brown fat in humans may explain the susceptibility to obesity. However, from evidence on the inability of ephedrine or beta-3 adrenergic agonists to induce BAT thermogenesis, it was concluded that the thermogenic role of BAT was unimportant in adult humans largely because humans had low numbers of brown adipocytes. Solid evidence on the actual numbers of brown adipocytes in humans was not available. We are now re-evaluating the role of BAT for the treatment of obesity given the following recent observations (i) studies in nuclear medicine by using PET/CT scanning reveal the presence of BAT in adult humans; and (ii) recent data suggest that a new transcription factor called PDRM16 may control the induction of BAT. These recent discoveries should revamp our effort to target the molecular development of brown adipogenesis in the treatment of obesity.
doi:10.1111/j.1467-789X.2008.00559.x
PMCID: PMC3960797  PMID: 19175509
Brown adipose tissue; obesity; PRDM16
2.  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
3.  An abbreviated history of the ear: from Renaissance to present. 
In this article we discuss important discoveries in relation to the anatomy and physiology of the ear from Renaissance to present. Before the Renaissance, there was a paucity of knowledge of the anatomy of the ear, because of the relative inaccessibility of the temporal bone and the general perception that human dissections should not be conducted. It was not until the sixteenth century that the middle ear was described with detail. Further progress would be made between the sixteenth and eighteenth century in describing the inner ear. In the nineteenth century, technological advancement permitted a description of the cells and structures that constitute the cochlea. Von Helmholtz made further progress in hearing physiology when he postulated his resonance theory and later von Békésy when he observed a traveling wave in human cadavers within the cochlea. Brownell later made a major advance when he discovered that the ear has a mechanism for sound amplification, via outer hair cell electromotility.
Images
PMCID: PMC2582694  PMID: 15369636
4.  Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol 
Pharmacological reviews  2006;58(1):87-114.
The prototypical xanthine oxidase (XO) inhibitor allopurinol, has been the cornerstone of the clinical management of gout and conditions associated with hyperuricemia for several decades. More recent data indicate that XO also plays an important role in various forms of ischemic and other types of tissue and vascular injuries, inflammatory diseases, and chronic heart failure. Allopurinol and its active metabolite oxypurinol showed considerable promise in the treatment of these conditions both in experimental animals and in small-scale human clinical trials. Although some of the beneficial effects of these compounds may be unrelated to the inhibition of the XO, the encouraging findings rekindled significant interest in the development of additional, novel series of XO inhibitors for various therapeutic indications. Here we present a critical overview of the effects of XO inhibitors in various pathophysiological conditions and also review the various emerging therapeutic strategies offered by this approach.
doi:10.1124/pr.58.1.6
PMCID: PMC2233605  PMID: 16507884
5.  A counting renaissance: combining stochastic mapping and empirical Bayes to quickly detect amino acid sites under positive selection 
Bioinformatics  2012;28(24):3248-3256.
Motivation: Statistical methods for comparing relative rates of synonymous and non-synonymous substitutions maintain a central role in detecting positive selection. To identify selection, researchers often estimate the ratio of these relative rates () at individual alignment sites. Fitting a codon substitution model that captures heterogeneity in across sites provides a reliable way to perform such estimation, but it remains computationally prohibitive for massive datasets. By using crude estimates of the numbers of synonymous and non-synonymous substitutions at each site, counting approaches scale well to large datasets, but they fail to account for ancestral state reconstruction uncertainty and to provide site-specific estimates.
Results: We propose a hybrid solution that borrows the computational strength of counting methods, but augments these methods with empirical Bayes modeling to produce a relatively fast and reliable method capable of estimating site-specific values in large datasets. Importantly, our hybrid approach, set in a Bayesian framework, integrates over the posterior distribution of phylogenies and ancestral reconstructions to quantify uncertainty about site-specific estimates. Simulations demonstrate that this method competes well with more-principled statistical procedures and, in some cases, even outperforms them. We illustrate the utility of our method using human immunodeficiency virus, feline panleukopenia and canine parvovirus evolution examples.
Availability: Renaissance counting is implemented in the development branch of BEAST, freely available at http://code.google.com/p/beast-mcmc/. The method will be made available in the next public release of the package, including support to set up analyses in BEAUti.
Contact: philippe.lemey@rega.kuleuven.be or msuchard@ucla.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts580
PMCID: PMC3579240  PMID: 23064000
6.  A Renaissance for Antisense Oligonucleotide Drugs in Neurology 
Archives of neurology  2009;66(1):32-38.
Antisense oligonucleotides are short nucleic acid sequences designed for use as small-molecule drugs. They recognize and bind to specific messenger RNA (mRNA) or pre-mRNA sequences to create small double-stranded regions of the target mRNA that alter mRNA splicing patterns or inhibit protein translation. Antisense approaches have been actively pursued as a form of molecular medicine for more than 20 years, but only one has been translated to a marketed drug (intraocular human immunodeficiency virus treatment). Two recent advances foreshadow a change in clinical applications of antisense strategies. First is the development of synthetic DNA analogues that show outstanding stability and sequence specificity yet little or no binding to modulator proteins. Second is the publication of impressive preclinical and clinical data using antisense in an exon-skipping strategy to increase dystrophin production in Duchenne muscular dystrophy. As long-standing barriers are successfully circumvented, attention turns toward scale-up of production, long-term toxicity studies, and the challenges to traditional drug regulatory attitudes presented by tightly targeted sequence-specific drugs.
doi:10.1001/archneurol.2008.540
PMCID: PMC4111150  PMID: 19139297
7.  The Renaissance and the universal surgeon: Giovanni Andrea Della Croce, a master of traumatology 
International Orthopaedics  2013;37(12):2523-2528.
All the medical knowledge of all time in one book, the universal and perfect manual for the Renaissance surgeon, and the man who wrote it. This paper depicts the life and works of Giovanni Andrea della Croce, a 16th Century physician and surgeon, who, endowed with true spirit of Renaissance humanism, wanted to teach and share all his medical knowledge through his opus magnum, titled “Universal Surgery Complete with All the Relevant Parts for the Optimum Surgeon”. An extraordinary book which truly represents a defining moment and a founding stone for traumatology, written by a lesser known historical personality, but nonetheless the Renaissance Master of Traumatology.
doi:10.1007/s00264-013-2111-2
PMCID: PMC3843219  PMID: 24173678
History of surgery; Ancient traumatology; Giovanni Andrea Della Croce; Renaissance
8.  Genomics and the renaissance of generalism 
Genome Biology  2000;1(1):reports411.1-reports411.2.
A meeting report of the sessions on human, eukaryotic and bacterial genome sequencing at the American Society for Microbiology and Institut Pasteur joint conference: Genomes 2000 International Conference on Microbial and Model Genomes, Paris, April 11-15, 2000
PMCID: PMC138831
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
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(4):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.  The physiological challenges of the 1952 Copenhagen poliomyelitis epidemic and a renaissance in clinical respiratory physiology 
The 1952 Copenhagen poliomyelitis epidemic provided extraordinary challenges in applied physiology. Over 300 patients developed respiratory paralysis within a few weeks, and the ventilator facilities at the infectious disease hospital were completely overwhelmed. The heroic solution was to call upon 200 medical students to provide round-the-clock manual ventilation using a rubber bag attached to a tracheostomy tube. Some patients were ventilated in this way for several weeks. A second challenge was to understand the gas exchange and acid-base status of these patients. At the onset of the epidemic, the only measurement routinely available in the hospital was the carbon dioxide concentration in the blood, and the high values were initially misinterpreted as a mysterious “alkalosis.” However, pH measurements were quickly instituted, the PCO2 was shown to be high, and modern clinical respiratory acid-base physiology was born. Taking a broader view, the problems highlighted by the epidemic underscored the gap between recent advances made by physiologists and their application to the clinical environment. However, the 1950s ushered in a renaissance in clinical respiratory physiology. In 1950 the coverage of respiratory physiology in textbooks was often woefully inadequate, but the decade saw major advances in topics such as mechanics and gas exchange. An important development was the translation of the new knowledge from departments of physiology to the clinical setting. In many respects, this period was therefore the beginning of modern clinical respiratory physiology.
doi:10.1152/japplphysiol.00184.2005
PMCID: PMC1351016  PMID: 16020437
pulmonary gas exchange; pulmonary mechanics; mechanical ventilation; acid-base balance; clinical physiology
25.  The renaissance of palladium(II)-catalyzed oxidation chemistry 
Organic & biomolecular chemistry  2004;2(18):2551-2554.
Palladium(II)-catalyzed oxidations constitute a paramount reaction class but have remained immature over the past few decades. Recently, this field has reappeared at the forefront of organometallic catalysis. This emerging area article outlines recent developments in palladium(II)-catalyzed oxidation chemistry with discussion of potential future growth.
doi:10.1039/B409127M
PMCID: PMC2667868  PMID: 15351815

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