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1.  Membrane protein structure determination — The next generation☆☆☆ 
Biochimica et Biophysica Acta  2014;1838(1):78-87.
The field of Membrane Protein Structural Biology has grown significantly since its first landmark in 1985 with the first three-dimensional atomic resolution structure of a membrane protein. Nearly twenty-six years later, the crystal structure of the beta2 adrenergic receptor in complex with G protein has contributed to another landmark in the field leading to the 2012 Nobel Prize in Chemistry. At present, more than 350 unique membrane protein structures solved by X-ray crystallography (http://blanco.biomol.uci.edu/mpstruc/exp/list, Stephen White Lab at UC Irvine) are available in the Protein Data Bank. The advent of genomics and proteomics initiatives combined with high-throughput technologies, such as automation, miniaturization, integration and third-generation synchrotrons, has enhanced membrane protein structure determination rate. X-ray crystallography is still the only method capable of providing detailed information on how ligands, cofactors, and ions interact with proteins, and is therefore a powerful tool in biochemistry and drug discovery. Yet the growth of membrane protein crystals suitable for X-ray diffraction studies amazingly remains a fine art and a major bottleneck in the field. It is often necessary to apply as many innovative approaches as possible. In this review we draw attention to the latest methods and strategies for the production of suitable crystals for membrane protein structure determination. In addition we also highlight the impact that third-generation synchrotron radiation has made in the field, summarizing the latest strategies used at synchrotron beamlines for screening and data collection from such demanding crystals. This article is part of a Special Issue entitled: Structural and biophysical characterisation of membrane protein-ligand binding.
Graphical abstract
Highlights
•Overview of the most recent advances regarding the growth of membrane protein crystals•Rational design of new crystallization screens for membrane proteins•New automated method for dehydration of membrane proteins•High-throughput approach in seeding of membrane protein crystals•Recent developments in membrane protein structure determination
doi:10.1016/j.bbamem.2013.07.010
PMCID: PMC3898769  PMID: 23860256
Membrane protein; Crystal dehydration; Crystal seeding; Macromolecular crystallography; In situ data collection; XFEL
2.  Environmental air toxics: role in asthma occurrence? 
Environmental Health Perspectives  2002;110(Suppl 4):501-504.
The National Urban Air Toxics Research Center (NUATRC) hosted its first scientific workshop in 1994 that focused on possible relationships between air toxics and asthma. From that meeting came recommendations for future research including a need for more complete individual personal exposure assessments so that determinations of personal exposures to pollutants could be made. In the spring of 2001, NUATRC held a second such workshop to review progress made in this area during the intervening 7 years. Peer-reviewed articles from the workshop are published in this issue of (italic)Environmental Health Perspectives Supplements(/italic). As in 1994, academic, government, and industry scientists participated. Dave Guinnup of the Environmental Protection Agency discussed the nature of air toxics, their definition, and the basis for federal regulation. George Leikauf from the University of Cincinnati reviewed the 1994 workshop and subsequent research in this field. Current research funded by NUATRC that is addressing individual personal exposure was presented by Clifford Weisel (Environmental and Occupational Health Sciences Institute, University of Medicine and Dentistry of New Jersey), Patrick Kinney (Columbia University) and Candis Claiborn (Washington State University). David Corry from Baylor College of Medicine highlighted new insights into asthma pathogenesis while Stephen Redd from the Centers for Disease Control presented an overview of asthma epidemiology as well as the societal costs of the disease. Mary White (Agency for Toxic Substances and Disease Registry) discussed recent epidemiologic investigations by public health agencies into community concerns about asthma and hazardous air pollutants. David Peden (University of North Carolina) reviewed scientific studies into the links between asthma and air toxics as well as criteria air pollutants. In a session on occupational asthma, Lee Petsonk (National Institute for Occupational Safety and Health) discussed risk factors for work-related asthma, whereas Ralph Delfino (University of California, Irvine) addressed limitations of extrapolating from occupational asthma to asthma in the general population. These presentations were followed by panel discussions focusing on future research programs, both for NUATRC and similar research institutions. Recommendations for future research included improved assessments of personal exposure to air toxics as well as research focused on specific hazardous air pollutants. The latter recommendation was based on medical literature that suggests certain pollutants from the list of 188 air toxics are most likely to adversely affect respiratory health.
PMCID: PMC1241199  PMID: 12194880
3.  The Alternating Access Transport Mechanism in LacY 
The Journal of Membrane Biology  2010;239(1-2):85-93.
Lactose permease of Escherichia coli (LacY) is highly dynamic, and sugar binding causes closing of a large inward-facing cavity with opening of a wide outward-facing hydrophilic cavity. Therefore, lactose/H+ symport via LacY very likely involves a global conformational change that allows alternating access of single sugar- and H+-binding sites to either side of the membrane. Here, in honor of Stephan H. White’s seventieth birthday, we review in camera the various biochemical/biophysical approaches that provide experimental evidence for the alternating access mechanism.
doi:10.1007/s00232-010-9327-5
PMCID: PMC3030946  PMID: 21161516
Lactose; Permease; Symport; Transport; Membrane; Membrane protein
4.  The Palade Symposium: Celebrating Cell Biology at Its Best 
Molecular Biology of the Cell  2010;21(14):2367-2370.
A symposium was held at the University of California, San Diego, to honor the contributions of Nobel Laureate, George Palade, to cell biology. The speakers included Günter Blobel, on the structure and function of nuclear pore complexes; Peter Walter, on the unfolded protein response in health and disease; Randy Schekman, on human disease-linked mutations in the COPII machinery; Scott Emr, on the regulation of plasma membrane composition by selective endocytosis; Roger Kornberg, on the structure and function of the transcription machinery; Peter Novick, on the regulation of rab GTPases along the secretory pathway; Jim Spudich, on the mechanism of the enigmatic myosin VI motor; and Joe Goldstein, on the function of the Niemann-Pick C (NPC)-linked gene products, NPC1 and NPC2, in cholesterol transport. Their work showcased the multidisciplinary nature, diversity, and vitality of cell biology. In the words of George Palade, their talks also illustrated “how cell biology could be used to understand disease and how disease could be used to discover normal cell biology.” An integrated understanding of the cellular machinery will be essential in tackling the plethora of questions and challenges posed by completion of the human genome and for understanding the molecular mechanisms underlying human disease.
doi:10.1091/mbc.E10-03-0179
PMCID: PMC2903666  PMID: 20505070
5.  Rapid Sampling of Molecular Motions with Prior Information Constraints 
PLoS Computational Biology  2009;5(2):e1000295.
Proteins are active, flexible machines that perform a range of different functions. Innovative experimental approaches may now provide limited partial information about conformational changes along motion pathways of proteins. There is therefore a need for computational approaches that can efficiently incorporate prior information into motion prediction schemes. In this paper, we present PathRover, a general setup designed for the integration of prior information into the motion planning algorithm of rapidly exploring random trees (RRT). Each suggested motion pathway comprises a sequence of low-energy clash-free conformations that satisfy an arbitrary number of prior information constraints. These constraints can be derived from experimental data or from expert intuition about the motion. The incorporation of prior information is very straightforward and significantly narrows down the vast search in the typically high-dimensional conformational space, leading to dramatic reduction in running time. To allow the use of state-of-the-art energy functions and conformational sampling, we have integrated this framework into Rosetta, an accurate protocol for diverse types of structural modeling. The suggested framework can serve as an effective complementary tool for molecular dynamics, Normal Mode Analysis, and other prevalent techniques for predicting motion in proteins. We applied our framework to three different model systems. We show that a limited set of experimentally motivated constraints may effectively bias the simulations toward diverse predicates in an outright fashion, from distance constraints to enforcement of loop closure. In particular, our analysis sheds light on mechanisms of protein domain swapping and on the role of different residues in the motion.
Author Summary
Incorporating external knowledge into computational frameworks is a challenge of prime importance in many fields of biological research. In this study, we show how computational power can be harnessed to make use of limited external information and to more effectively simulate the molecular motion of proteins. While experimentally solved protein structures restrict our knowledge to static molecular “snapshots”, a vast number of proteins are flexible entities that constantly change shape. Protein motion is therefore intrinsically related to protein function. State-of-the-art experimental approaches are still limited in the information that they provide about protein motion. Therefore, we suggest here a very general computational framework that can take into account diverse external constraints and include experimental information or expert intuition. We explore in detail several biological systems of prime interest, including domain swapping and substrate binding, and show how limited partial information enhances the accuracy of predictions. Suggested motion pathways form detailed lab-testable hypotheses and can be of great interest to both experimentalists and theoreticians.
doi:10.1371/journal.pcbi.1000295
PMCID: PMC2637990  PMID: 19247429
6.  Stress symposium in Johannesburg: plants versus humans 
Cell Stress & Chaperones  1998;3(3):143-146.
On 18 February 1998, a ‘Stress symposium’ was held at the Rand Afrikaans University (RAU) in Johannesburg, South Africa. The meeting brought together people from both the plant and the human oxidative stress field, which was exemplified by a talk entitled ‘Heat shock proteins in host-pathogen interactions: plants versus humans’. There were moments when it appeared as if the main difference between plants and humans was, as sung by Julos Beaucarne, that ‘the human plant is the only one to be able to water itself…’
PMCID: PMC312957  PMID: 9764753
7.  The Second Canadian Symposium on Hepatitis C Virus: A call to action 
In Canada, hepatitis C virus (HCV) infection results in considerable morbidity, mortality and health-related costs. Within the next three to 10 years, it is expected that tolerable, short-duration (12 to 24 weeks) therapies capable of curing >90% of those who undergo treatment will be approved. Given that most of those already infected are aging and at risk for progressive liver disease, building research-based interdisciplinary prevention, care and treatment capacity is an urgent priority. In an effort to increase the dissemination of knowledge in Canada in this rapidly advancing field, the National CIHR Research Training Program in Hepatitis C (NCRTP-HepC) established an annual interdisciplinary Canadian Symposium on Hepatitis C Virus. The first symposium was held in Montreal, Quebec, in 2012, and the second symposium was held in Victoria, British Columbia, in 2013. The current article presents highlights from the 2013 meeting. It summarizes recent advances in HCV research in Canada and internationally, and presents the consensus of the meeting participants that Canada would benefit from having its own national HCV strategy to identify critical gaps in policies and programs to more effectively address the challenges of expanding HCV screening and treatment.
PMCID: PMC3816942  PMID: 24199209
Biomedical; Canada; Epidemiology; HCV; Public health; Social science
10.  A celebration of mechanics: from nano to macro. The J. Michael T. Thompson Festschrift issue 
This Theme Issue is dedicated to the topic ‘Mechanics: from nano to macro’ and marks the 75th birthday of Dr J. Michael T. Thompson, Fellow of the Royal Society, whose current affiliations are as follows: (i) Honorary Fellow, Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge; (ii) Emeritus Professor of Nonlinear Dynamics, Department of Civil, Environmental and Geomatic Engineering, University College London; and (iii) Professor of Theoretical and Applied Dynamics (Distinguished Sixth Century Chair, part-time), University of Aberdeen. He also serves as Chairman of the Board of Directors at ES-Consult (consulting engineers) in Copenhagen, Denmark. The pertinent question that arises from the very start is: should we first salute Michael and then describe the Theme Issue, or vice versa? Indeed, according to Blaise Pascal (1623–1662), the last thing one discovers in composing a work is what to put first. I would like to take the liberty of deviating from the tradition of the Philosophical Transactions and start with the tribute to Michael; after all he is the prime cause of this Theme Issue.
doi:10.1098/rsta.2013.0121
PMCID: PMC3682718  PMID: 23690647
theoretical and applied mechanics; nanomechanics; macromechanics
11.  The Global Cancer Genomics Consortium’s Second Annual Symposium 
Genes & Cancer  2013;4(5-6):196-200.
The Second Annual Symposium of the Global Cancer Genomics Consortium (GCGC) was held at the Tata Memorial Center in Mumbai, India, from November 19 to 20, 2012. Founded in late 2010, the GCGC aims to provide a platform for highly productive, collaborative efforts on next-generation cancer research through bridging the latest scientific and technology developments with clinical oncology challenges. This year’s presenters brought together highly innovative interdisciplinary views and strategies to meet major challenges in cancer research. The symposium featured 3 major themes: OMICS approaches toward the identification of cancer molecular drivers, single-cell analysis in cancer, and clinical and translational genomics. Each theme was represented in presentations of new findings, with an obvious implication in cross-disciplinary components of OMICs and an overwhelming participation by students. In summary, the GCGC symposium provided a discussion and congregation of the latest advances in basic and translational cancer research and offered the participants with a highly cooperative network environment for future collaboration.
doi:10.1177/1947601913484582
PMCID: PMC3782003
genomics medicine; anticancer target; cancer therapy
12.  A Bulk-Water-Dependent Desolvation Energy Model for Analyzing the Effects of Secondary Solutes on Biological Equilibria† 
Biochemistry  2011;50(12):2004-2012.
A new phenomenological model for interpreting solute effects on biological equilibria is presented. The model attributes changes in equilibria to differences in the desolvation energy of the reacting species which, in turn, reflect changes in the free energy of the bulk water on addition of secondary solutes. The desolvation approach differs notably from other solute models by treating the free energy of bulk water as a variable and by not ascribing the observed shifts in reaction equilibria to accumulation or depletion of solutes next to the surfaces of the reacting species. On the contrary, the partitioning of solutes is viewed as a manifestation of the different subpopulations of water that arise in response to the surface boundary conditions. A thermodynamic framework consistent with the proposed model is used to derive a relationship for a specific reaction, an aqueous solubility equilibrium, in two or more solutions. The resulting equation reconciles some potential issues with the transfer free energy model of Tanford. Application of the desolvation energy model to the analysis of a two-state protein folding equilibrium is discussed and contrasted to the application of two other solute models developed by Timasheff and by Parsegian. Future tabulation of solvation energies and bulk water energies may allow biophysical chemists to confirm the mechanism by which secondary solutes influence binding and conformational equilibria and may provide a common ground for experimentalists and theoreticians to compare and evaluate their results.
doi:10.1021/bi1017717
PMCID: PMC3062708  PMID: 21284393
13.  Proceedings of the First International Optogenetic Therapies for Vision Symposium 
Optogenetics is a research field that uses gene therapy to deliver a gene encoding a light-activated protein to cells providing light-regulated control of targeted cell pathways. The technology is a popular tool in many fields of neuroscience, used to transiently switch cells on and off, for example, to map neural circuits. In inherited retinal degenerative diseases, where loss of vision results from the loss of photoreceptors, optogenetics can be applied to either augment the function of surviving photoreceptors or confer light sensitivity to naturally nonlight sensitive retinal cells, such as a bipolar cells. This can be achieved either by the light sensitive protein integrating with native internal signaling pathways, or by using a dual function membrane protein that integrates light signaling with an ion channel or pump activity. Exposing treated cells to light of the correct wavelength activates the protein, resulting in cellular depolarization or hyperpolarization that triggers neurological signaling to the visual cortex.
While there is a lot of interest in optogenetics as a pan-disease clinical treatment for end-stage application in the inherited degenerative diseases of the retina, research to date has been limited to nonhuman clinical studies. To address the clinical translational needs of this technology, the Foundation Fighting Blindness and Massachusetts Eye and Ear Infirmary cohosted an International Optogenetic Therapies for Vision Workshop, which was held at Massachusetts Eye and Ear Infirmary, Boston, Massachusetts on June 1, 2012.
doi:10.1167/tvst.2.7.4
PMCID: PMC3860355  PMID: 24349882
optogenetics; vision; retina; gene therapy
14.  21st Birthday Drinking and Associated Physical Consequences and Behavioral Risks 
Twenty-first birthday celebrations often involve dangerously high levels of alcohol consumption, yet little is known about risk factors for excessive drinking on this occasion. Participants (N = 150) from a larger prospective study who consumed at least one drink during their celebration completed questionnaires and semi-structured interviews about their 21st birthday within four days after the event. Assessments were designed to characterize 21st birthday alcohol use, adjusted for alcohol content, as well as situational/contextual factors (e.g., celebration location, peer influence) that contribute to event-level drinking. Participants reported an average of 10.85 drinks (9.76 adjusted drinks), with experienced drinkers consuming significantly more than relatively naïve drinkers who had no previous binge or drunken episodes. Men consumed more drinks, whereas age of first drunken episode and heavier drinking during the 3-months preceding the 21st birthday predicted higher estimated blood alcohol concentrations (eBACs) on the 21st birthday. Celebrating in bars and engaging in birthday-specific drinking traditions (free drinks at bars) explained additional variance in 21st birthday eBACs. Both physical consequences (e.g., blacking out or having a hangover) and behavioral risks (e.g., sexually provocative behaviors) were prevalent and were predicted by higher eBACs. Together these findings indicate that 21st birthday celebrations are associated with heavy drinking and a variety of physical consequences and behavioral risks.
doi:10.1037/a0025209
PMCID: PMC3232305  PMID: 21895347
21st birthday; alcohol; alcohol-related problems; behavioral risk; physical consequences
15.  A Prevalent Variant in PPP1R3A Impairs Glycogen Synthesis and Reduces Muscle Glycogen Content in Humans and Mice 
PLoS Medicine  2008;5(1):e27.
Background
Stored glycogen is an important source of energy for skeletal muscle. Human genetic disorders primarily affecting skeletal muscle glycogen turnover are well-recognised, but rare. We previously reported that a frameshift/premature stop mutation in PPP1R3A, the gene encoding RGL, a key regulator of muscle glycogen metabolism, was present in 1.36% of participants from a population of white individuals in the UK. However, the functional implications of the mutation were not known. The objective of this study was to characterise the molecular and physiological consequences of this genetic variant.
Methods and Findings
In this study we found a similar prevalence of the variant in an independent UK white population of 744 participants (1.46%) and, using in vivo 13C magnetic resonance spectroscopy studies, demonstrate that human carriers (n = 6) of the variant have low basal (65% lower, p = 0.002) and postprandial muscle glycogen levels. Mice engineered to express the equivalent mutation had similarly decreased muscle glycogen levels (40% lower in heterozygous knock-in mice, p < 0.05). In muscle tissue from these mice, failure of the truncated mutant to bind glycogen and colocalize with glycogen synthase (GS) decreased GS and increased glycogen phosphorylase activity states, which account for the decreased glycogen content.
Conclusions
Thus, PPP1R3A C1984ΔAG (stop codon 668) is, to our knowledge, the first prevalent mutation described that directly impairs glycogen synthesis and decreases glycogen levels in human skeletal muscle. The fact that it is present in ∼1 in 70 UK whites increases the potential biomedical relevance of these observations.
Stephen O'Rahilly and colleagues describe the effect of a mutation inPPP1R3A, present in 1.36% of participants from one UK population, that directly impairs glycogen synthesis and decreases glycogen levels in human skeletal muscle.
Editors' Summary
Background.
The human body gets the energy it needs for day-to-day living from food in a process called metabolism. However, not all the energy released by metabolism is used immediately. Some is stored in skeletal muscles as glycogen, a glucose polymer that is used during high intensity exercise. After eating, chemicals in the digestive system release glucose (a type of sugar) from food into the bloodstream where it triggers insulin release from the pancreas. Insulin instructs muscle, liver and fat cells to remove glucose from the bloodstream to keep the amount of sugar in the blood at a safe level. The cells use the glucose immediately as fuel or convert it into glycogen or fat for storage. Glycogen turnover (the depletion and replacement of glycogen stores) is tightly controlled by glycogen synthase and glycogen phosphorylase, enzymes that make and destroy glycogen, respectively. A third enzyme called protein phosphatase 1 promotes net glycogen synthesis by activating glycogen synthase and inactivating glycogen phosphorylase. The activity of protein phosphatase 1 is regulated by a family of “targeting subunits.” In muscle, one of these targeting subunits, called RGL, facilitates protein phosphatase 1 action on glycogen synthase and glycogen phosphorylase.
Why Was This Study Done?
Several known human genetic disorders affect the breakdown of muscle glycogen but few genetic changes (mutations) have been found that decrease the synthesis of muscle glycogen. Researchers are interested in discovering mutations that affect glycogen turnover and other aspects of metabolism because some of these may be involved in the development of diabetes, an important metabolic disorder characterized by high blood sugar levels. In this study, the researchers have investigated how a recently identified mutation in PPP1R3A, the gene that encodes RGL, affects glycogen synthesis. This mutation—PPP1R3A FS—was previously found in 1.36% of a UK white population. It causes the production of a short version of RGL that lacks the part of the molecule that tethers RGL to a cellular structure called the sarcoplasmic reticulum but leaves its glycogen binding domain intact.
What Did the Researchers Do and Find?
To confirm that PPP1R3A FS is a common mutation in the UK white population, the researchers sequenced the gene in 744 healthy adults enrolled in the Oxford Biobank (which hopes to uncover metabolically important genetic variations by monitoring the health of a large number of 30- to 50-year-old people from whom DNA has been collected). 1.46% of these people had the PPP1R3A FS mutation. To examine glycogen storage in carriers of the mutation, the researchers used a technique called in vivo 13C magnetic resonance spectroscopy. Basal muscle glycogen levels and those reached after a meal were lower in these individuals than in people without the mutation but their blood sugar and insulin levels were normal. Finally, to examine how the mutation reduces muscle glycogen, the researchers made mice carrying the PPP1R3A FS mutation. Like the human carriers, these mice had less glycogen than normal in their muscles. Unexpectedly, in biochemical experiments the truncated RGL protein made by the mutant mice did not bind to glycogen or co-localize with glycogen synthase. This lack of binding decreased the activity of glycogen synthase and increased the activity of glycogen phosphorylase, thus decreasing muscle glycogen.
What Do These Findings Mean?
These findings identify the PPP1R3A FS mutation as the first prevalent mutation known to impair glycogen synthesis and to decrease glycogen levels in human skeletal muscles. They also confirm that this mutation is very common in UK whites. Although these human carriers do not report any exercise intolerance, detailed studies are needed to test whether the mutation has any effect on skeletal muscle performance. In addition, suggest the researchers, the mutation might be involved in the development of type 2 diabetes. Impaired insulin-stimulated glycogen synthesis, which is a feature of insulin-resistant muscle and liver cells, is thought to be a key event in the development of type 2 diabetes. Although some previous results indicate that the PPP1R3A FS mutations can sometimes predispose people to develop insulin resistance, only a large population-based study in multiple ethnic groups will reveal whether the PPP1R3A FS mutation has an important impact on the development of type 2 diabetes.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050027.
Wikipedia has pages on metabolism and on glycogen (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The MedlinePlus encyclopedia provides information about diabetes (in English and Spanish)
The UK Biobank is looking for genetic variations among human populations that are associated with metabolic and other disorders
Web sites are available with brief descriptions of the research programs of Stephen O'Rahilly and Anna DePaoli-Roach
doi:10.1371/journal.pmed.0050027
PMCID: PMC2214798  PMID: 18232732
16.  Kitasato Symposium 2009: New Prospects for Cytokine Inhibition 
The Kitasato Symposium 2009: New Prospects for Cytokine Inhibition was held in Berlin, Germany from 7 to 9 May 2009. The key aims of this meeting were to bring together a group of front-line researchers and rheumatologists to evaluate the use of cytokine blockade and to examine the role of certain cytokines in the pathogenesis of rheumatoid arthritis and other autoimmune diseases. A keynote lecture delivered by Professor Jean-Michel Dayer provided an up-to-date overview of the interactions occurring between the immune system and acute phase proteins. Other speakers discussed the role of cytokines in rheumatoid arthritis, including their role in joint destruction, as well as their regulatory role upon T cells and B cells. The involvement of cytokines in other autoimmune diseases was also addressed.
doi:10.1186/ar2857
PMCID: PMC3003512  PMID: 20067593
17.  New experimental and theoretical investigations of hematopoietic stem cells and chronic myeloid leukemia 
We report on a focused workshop of The Leukemia and Lymphoma Society that was held at Goldsmiths, University of London in 2008. During this workshop we discussed new clinical and experimental data in chronic myeloid leukemia (CML) research, particularly focusing on the validity (or otherwise) of corresponding mathematical models and simulations. We were specifically interested in whether the models could shed light on any of the fundamental mechanisms underlying this disease. Moreover, we were aiming to form a new community of clinicians and modelers looking at this disease and to define a common language and theoretical framework within which collaboration could flourish.
The workshop showed the role that models can play, not just in trying to fit to existing data or predicting what individual mechanisms or system behaviors might occur, but also in challenging the orthodoxy of the concept of a stem cell and concepts such as “differentiation” and “determination”. For years the prevailing view of a stem cell has been an entity (object) with a fixed set of behaviors and with a pre-determined fate. New perspectives in modeling, coupled with the new data that are being accumulated in the genesis of CML and its treatment, questions these assumptions. We propose how we can reach a consensus about a functional view of stem cells in a more continuous and flexible way and how, within this context, we can investigate the significance of modeling results and how they might impact on our interpretation of experimental observations and the development of new clinical strategies.
This paper reports on the workshop and the state-of-the-art models and data from experimental and clinical trials, and sets out a roadmap for more interdisciplinary collaboration between modelers, wet-lab experimentalists, and clinicians interested in CML. It is our strong belief that a more integrated and coherent interdisciplinary approach will further advance the treatment of CML in future years.
doi:10.1016/j.bcmd.2009.03.003
PMCID: PMC3741041  PMID: 19411181
Mathematical modelling; Computer simulation; Hematopoietic stem cells; Chronic myeloid leukemia
18.  A Randomized Controlled Trial of Event Specific Prevention Strategies for Reducing Problematic Drinking Associated with 21st Birthday Celebrations 
Objective
While research has documented heavy drinking practices and associated negative consequences of college students turning 21, few studies have examined prevention efforts aimed to reduce high-risk drinking during 21st birthday celebrations. The present study evaluated the comparative efficacy of a general prevention effort (i.e., BASICS) and event specific prevention in reducing 21st birthday drinking and related negative consequences. Furthermore, this study evaluated inclusion of peers in interventions and mode of intervention delivery (i.e., in-person vs. web).
Method
Participants included 599 college students (46% male) who intended to consume at least five/four drinks (men/women respectively) on their 21st birthday. After completing a screening/baseline assessment approximately one week before turning 21, participants were randomly assigned to one of six conditions: 21st birthday in-person BASICS, 21st birthday web BASICS, 21st birthday in-person BASICS plus friend intervention, 21st birthday web BASICS plus friend intervention, BASICS, or an attention control. A follow-up assessment was completed approximately one week after students’ birthdays.
Results
Results indicated a significant intervention effect for BASICS in reducing blood alcohol content reached and number of negative consequences experienced. All three in-person interventions reduced negative consequences experienced. Results for the web-based interventions varied by drinking outcome and whether or not a friend was included.
Conclusions
Overall, results provide support for both general intervention and ESP approaches across modalities for reducing extreme drinking and negative consequences associated with turning 21. These results suggest there are several promising options for campuses seeking to reduce both use and consequences associated with 21st birthday celebrations.
doi:10.1037/a0029480
PMCID: PMC3458124  PMID: 22823855
Alcohol; alcohol-related problems; college students; event-specific drinking; event-specific prevention; 21st birthday
19.  A Boost for the Emerging Field of RNA Nanotechnology 
ACS Nano  2011;5(5):3405-3418.
This Nano Focus article highlights recent advances in RNA nanotechnology as presented at the First International Conference of RNA Nanotechnology and Therapeutics, which took place in Cleveland, OH, USA (October 23–25, 2010) (http://www.eng.uc.edu/nanomedicine/RNA2010/), chaired by Peixuan Guo and co-chaired by David Rueda and Scott Tenenbaum. The conference was the first of its kind to bring together more than 30 invited speakers in the frontier of RNA nanotechnology from France, Sweden, South Korea, China, and throughout the United States to discuss RNA nanotechnology and its applications. It provided a platform for researchers from academia, government, and the pharmaceutical industry to share existing knowledge, vision, technology, and challenges in the field and promoted collaborations among researchers interested in advancing this emerging scientific discipline. The meeting covered a range of topics, including biophysical and single-molecule approaches for characterization of RNA nanostructures; structure studies on RNA nanoparticles by chemical or biochemical approaches, computation, prediction, and modeling of RNA nanoparticle structures; methods for the assembly of RNA nanoparticles; chemistry for RNA synthesis, conjugation, and labeling; and application of RNA nanoparticles in therapeutics. A special invited talk on the well-established principles of DNA nanotechnology was arranged to provide models for RNA nanotechnology. An Administrator from National Institutes of Health (NIH) National Cancer Institute (NCI) Alliance for Nanotechnology in Cancer discussed the current nanocancer research directions and future funding opportunities at NCI. As indicated by the feedback received from the invited speakers and the meeting participants, this meeting was extremely successful, exciting, and informative, covering many groundbreaking findings, pioneering ideas, and novel discoveries.
doi:10.1021/nn200989r
PMCID: PMC3102291  PMID: 21604810
20.  Presentation of the 2009 Morris F Collen Award to Betsy L Humphreys, with remarks from the recipient 
The American College of Medical Informatics is an honorary society established to recognize those who have made sustained contributions to the field. Its highest award, for lifetime achievement and contributions to the discipline of medical informatics, is the Morris F Collen Award. Dr Collen's own efforts as a pioneer in the field stand out as the embodiment of creativity, intellectual rigor, perseverance, and personal integrity. The Collen Award, given once a year, honors an individual whose attainments have, throughout a whole career, substantially advanced the science and art of biomedical informatics. In 2009, the college was proud to present the Collen Award to Betsy Humphreys, MLS, deputy director of the National Library of Medicine. Ms Humphreys has dedicated her career to enabling more effective integration and exchange of electronic information. Her work has involved new knowledge sources and innovative strategies for advancing health data standards to accomplish these goals. Ms Humphreys becomes the first librarian to receive the Collen Award. Dr Collen, on the occasion of his 96th birthday, personally presented the award to Ms Humphreys.
doi:10.1136/jamia.2010.005728
PMCID: PMC2995660  PMID: 20595319
21.  Genetics and the origin of species: the continuing synthesis a symposium in honor of Richard G. Harrison 
Genetica  2010;139(5):535-707.
This is a special issue of Genetica that has its origins in a symposium held in honor of Richard G. Harrison at Ithaca, New York on July 22–23. Former students of Rick Harrison organized the symposium and most of the speakers were former students, as well. The quality and breadth of the talks were a testament to Rick’s influence as a thinker, synthesizer, and mentor and it is only appropriate to reflect on Rick’s contributions to the fields of evolutionary ecology, systematics, and genetics in this preface to the symposium articles.
doi:10.1007/s10709-010-9518-0
PMCID: PMC3736974  PMID: 21152955
22.  21st Birthday Celebratory Drinking: Evaluation of a Personalized Normative Feedback Card Intervention 
This research was designed to evaluate a personalized normative feedback birthday card intervention aimed at reducing normative perceptions, alcohol consumption, and negative consequences associated with 21st birthday celebrations among college students (N = 281; 59.15% women). Students were randomly assigned to receive or not receive a birthday card about 1 week prior to their 21st birthday. Approximately 1 week following their birthday, students were asked to complete a brief survey concerning their birthday celebration activities. Findings indicated that the birthday card intervention was not successful at reducing drinking or consequences; however, the card did reduce normative misperceptions. Additional findings indicated that many students experienced negative consequences, such as passing out or driving after consuming alcohol. Combined, these findings suggest that prevention is needed for drinking associated with turning 21. However, prevention efforts should consist of more than a birthday card.
doi:10.1037/0893-164X.22.2.176
PMCID: PMC2758637  PMID: 18540715
21st birthday; alcohol; alcohol-related problems; social norms; personalized normative feedback
23.  Thermodynamics and Mechanics of Membrane Curvature Generation and Sensing by Proteins and Lipids 
Research investigating lipid membrane curvature generation and sensing is a rapidly developing frontier in membrane physical chemistry and biophysics. The fast recent progress is based on the discovery of a plethora of proteins involved in coupling membrane shape to cellular membrane function, the design of new quantitative experimental techniques to study aspects of membrane curvature, and the development of analytical theories and simulation techniques that allow a mechanistic interpretation of quantitative measurements. The present review first provides an overview of important classes of membrane proteins for which function is coupled to membrane curvature. We then survey several mechanisms that are assumed to underlie membrane curvature sensing and generation. Finally, we discuss relatively simple thermodynamic/mechanical models that allow quantitative interpretation of experimental observations.
doi:10.1146/annurev.physchem.012809.103450
PMCID: PMC4205088  PMID: 21219150
curvature-composition coupling; giant unilamellar vesicle; lipid membrane; tube
24.  The Brain Connectivity Workshops: Moving the frontiers of computational systems neuroscience 
NeuroImage  2008;42(1):1-9.
Understanding the link between neurobiology and cognition requires that neuroscience moves beyond mere structure-function correlations. An explicit systems perspective is needed in which putative mechanisms of how brain function is constrained by brain structure are mathematically formalized and made accessible for experimental investigation. Such a systems approach critically rests on a better understanding of brain connectivity in its various forms. Since 2002, frontier topics of connectivity and neural system analysis have been discussed in a multidisciplinary annual meeting, the Brain Connectivity Workshop (BCW), bringing together experimentalists and theorists from various fields. This article summarizes some of the main discussions at the two most recent workshops, 2006 at Sendai, Japan, and 2007 at Barcelona, Spain: (i) investigation of cortical micro- & macrocircuits, (ii) models of neural dynamics at multiple scales, (iii) analysis of “resting state” networks, and (iv) linking anatomical to functional connectivity. Finally, we outline some central challenges and research trajectories in computational systems neuroscience for the next years.
doi:10.1016/j.neuroimage.2008.04.167
PMCID: PMC2574909  PMID: 18511300
neural systems analysis; effective connectivity; nonlinear dynamics; fMRI; EEG; MEG; DCM; model comparison; resting state; microcircuits
25.  A Brief Review of the Biophysical Hallmarks of Metastatic Cancer Cells 
Cancer hallmarks  2013;1(2-3):59-66.
A hallmark of metastatic cancer cells is their invasion through the basal membrane and endothelial layer, which requires a highly elastic cytoskeleton and nucleus. Therefore, cellular deformability can serve as a universal biophysical marker for detecting a tumor’s propensity for invasion, migration, and metastasis. In this review, we define the importance of the biophysical features of cancer cells in tumor metastasis and summarize the state-of-the-art technology for the study of cell biomechanics. This review will serve as a brief introduction to the interdisciplinary character of cancer cell biophysics for cancer biologists, physicists, and engineers.
doi:10.1166/ch.2013.1010
PMCID: PMC4189832  PMID: 25309822
Cancer metastasis; Biophysics; Cell biomechanics; Microfluidics; Mechanobiology

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