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1.  The Ordospora colligata Genome: Evolution of Extreme Reduction in Microsporidia and Host-To-Parasite Horizontal Gene Transfer 
mBio  2015;6(1):e02400-14.
ABSTRACT 
Microsporidia are a group of obligate intracellular parasites that are best known for their unique infection mechanism and their unparalleled levels of genomic reduction and compaction. We sequenced the genome of Ordospora colligata, a gut parasite of the microcrustacean Daphnia sp. and the closest known relative to the microsporidia characterized by the most extreme genomic reduction, the model genus Encephalitozoon. We found that the O. colligata genome is as compact as those of Encephalitozoon spp., featuring few introns and a similar complement of about 2,000 genes, altogether showing that the extreme reduction took place before the origin of Encephalitozoon spp. and their adaptation to vertebrate hosts. We also found that the O. colligata genome has acquired by horizontal transfer from its animal host a septin that is structurally analogous to septin 7, a protein that plays a major role in the endocytosis-based invasion mechanism of the fungal pathogen Candida albicans. Microsporidian invasion is most often characterized by injection through a projectile tube, but microsporidia are also known to invade cells by inducing endocytosis. Given the function of septins in other systems, we hypothesize that the acquired septin could help O. colligata induce its uptake by mimicking host receptors.
Importance The smallest known eukaryotic genomes are found in members of the Encephalitozoon genus of microsporidian parasites. Their extreme compaction, however, is not characteristic of the group, whose genomes can differ by an order of magnitude. The processes and evolutionary forces that led the Encephalitozoon genomes to shed so much of their ancestral baggage are unclear. We sequenced the genome of Ordospora colligata, a parasite of the water flea Daphnia sp. and the closest known relative of Encephalitozoon species, and show that this extreme reduction predated the split between the two lineages. We also found that O. colligata has acquired a septin gene by host-to-parasite horizontal transfer and predicted that the encoded protein folds like a septin 7, which plays a major role in endocytosis. We hypothesize that this acquisition could help O. colligata parasitize its hosts by facilitating endocytic infection, a mechanism that occurs in microsporidia but that is not yet well understood.
Importance
The smallest known eukaryotic genomes are found in members of the Encephalitozoon genus of microsporidian parasites. Their extreme compaction, however, is not characteristic of the group, whose genomes can differ by an order of magnitude. The processes and evolutionary forces that led the Encephalitozoon genomes to shed so much of their ancestral baggage are unclear. We sequenced the genome of Ordospora colligata, a parasite of the water flea Daphnia sp. and the closest known relative of Encephalitozoon species, and show that this extreme reduction predated the split between the two lineages. We also found that O. colligata has acquired a septin gene by host-to-parasite horizontal transfer and predicted that the encoded protein folds like a septin 7, which plays a major role in endocytosis. We hypothesize that this acquisition could help O. colligata parasitize its hosts by facilitating endocytic infection, a mechanism that occurs in microsporidia but that is not yet well understood.
doi:10.1128/mBio.02400-14
PMCID: PMC4313915  PMID: 25587016
2.  Home-based Computer Assisted Arm Rehabilitation (hCAAR) robotic device for upper limb exercise after stroke: results of a feasibility study in home setting 
Background
Home-based robotic technologies may offer the possibility of self-directed upper limb exercise after stroke as a means of increasing the intensity of rehabilitation treatment. The current literature has a paucity of robotic devices that have been tested in a home environment. The aim of this research project was to evaluate a robotic device Home-based Computer Assisted Arm Rehabilitation (hCAAR) that can be used independently at home by stroke survivors with upper limb weakness.
Methods
hCAAR device comprises of a joystick handle moved by the weak upper limb to perform tasks on the computer screen. The device provides assistance to the movements depending on users ability. Nineteen participants (stroke survivors with upper limb weakness) were recruited. Outcome measures performed at baseline (A0), at end of 8-weeks of hCAAR use (A1) and 1 month after end of hCAAR use (A2) were: Optotrak kinematic variables, Fugl Meyer Upper Extremity motor subscale (FM-UE), Action Research Arm Test (ARAT), Medical Research Council (MRC) and Modified Ashworth Scale (MAS), Chedoke Arm and Hand Activity Inventory (CAHAI) and ABILHAND.
Results
Two participants were unable to use hCAAR: one due to severe paresis and the other due to personal problems. The remaining 17 participants were able to use the device independently in their home setting. No serious adverse events were reported. The median usage time was 433 minutes (IQR 250 – 791 min). A statistically significant improvement was observed in the kinematic and clinical outcomes at A1. The median gain in the scores at A1 were by: movement time 19%, path length 15% and jerk 19%, FM-UE 1 point, total MAS 1.5 point, total MRC 2 points, ARAT 3 points, CAHAI 5.5 points and ABILHAND 3 points. Three participants showed clinically significant improvement in all the clinical outcomes.
Conclusions
The hCAAR feasibility study is the first clinical study of its kind reported in the current literature; in this study, 17 participants used the robotic device independently for eight weeks in their own homes with minimal supervision from healthcare professionals. Statistically significant improvements were observed in the kinematic and clinical outcomes in the study.
doi:10.1186/1743-0003-11-163
PMCID: PMC4280043  PMID: 25495889
Cerebrovascular; Robot; Rehabilitation; Tele-rehabilitation
3.  Proteomics Indicators of the Rapidly Shifting Physiology from Whole Mountain Pine Beetle, Dendroctonus ponderosae (Coleoptera: Curculionidae), Adults during Early Host Colonization 
PLoS ONE  2014;9(10):e110673.
We developed proteome profiles for host colonizing mountain pine beetle adults, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae). Adult insects were fed in pairs on fresh host lodgepole pine, Pinus contorta Dougl. ex Loud, phloem tissue. The proteomes of fed individuals were monitored using iTRAQ and compared to those of starved beetles, revealing 757 and 739 expressed proteins in females and males, respectively, for which quantitative information was obtained. Overall functional category distributions were similar for males and females, with the majority of proteins falling under carbohydrate metabolism (glycolysis, gluconeogenesis, citric acid cycle), structure (cuticle, muscle, cytoskeleton), and protein and amino acid metabolism. Females had 23 proteins with levels that changed significantly with feeding (p<0.05, FDR<0.20), including chaperones and enzymes required for vitellogenesis. In males, levels of 29 proteins changed significantly with feeding (p<0.05, FDR<0.20), including chaperones as well as motor proteins. Only two proteins, both chaperones, exhibited a significant change in both females and males with feeding. Proteins with differential accumulation patterns in females exhibited higher fold changes with feeding than did those in males. This difference may be due to major and rapid physiological changes occurring in females upon finding a host tree during the physiological shift from dispersal to reproduction. The significant accumulation of chaperone proteins, a cytochrome P450, and a glutathione S-transferase, indicate secondary metabolite-induced stress physiology related to chemical detoxification during early host colonization. The females' activation of vitellogenin only after encountering a host indicates deliberate partitioning of resources and a balancing of the needs of dispersal and reproduction.
doi:10.1371/journal.pone.0110673
PMCID: PMC4215907  PMID: 25360753
4.  Strategies for Controlling Non-Transmissible Infection Outbreaks Using a Large Human Movement Data Set 
PLoS Computational Biology  2014;10(9):e1003809.
Prediction and control of the spread of infectious disease in human populations benefits greatly from our growing capacity to quantify human movement behavior. Here we develop a mathematical model for non-transmissible infections contracted from a localized environmental source, informed by a detailed description of movement patterns of the population of Great Britain. The model is applied to outbreaks of Legionnaires' disease, a potentially life-threatening form of pneumonia caused by the bacteria Legionella pneumophilia. We use case-report data from three recent outbreaks that have occurred in Great Britain where the source has already been identified by public health agencies. We first demonstrate that the amount of individual-level heterogeneity incorporated in the movement data greatly influences our ability to predict the source location. The most accurate predictions were obtained using reported travel histories to describe movements of infected individuals, but using detailed simulation models to estimate movement patterns offers an effective fast alternative. Secondly, once the source is identified, we show that our model can be used to accurately determine the population likely to have been exposed to the pathogen, and hence predict the residential locations of infected individuals. The results give rise to an effective control strategy that can be implemented rapidly in response to an outbreak.
Author Summary
Public health strategies for infectious disease control can benefit greatly from our growing capacity to predict human movement behaviour. This is facilitated by modern methods of electronic data generation and storage that allow us to track detailed human movement patterns. Here we develop a mathematical model of the dynamics of non-transmissible infections that is informed by a new data set describing detailed movements of the population of Great Britain. We apply the model to three outbreaks of Legionnaires' disease. We demonstrate how the method can assist during the crucial early stages of an outbreak by providing predictions of the infection source location and individuals with a high exposure risk.
doi:10.1371/journal.pcbi.1003809
PMCID: PMC4161289  PMID: 25211122
5.  A Complex Distribution of Elongation Family GTPases EF1A and EFL in Basal Alveolate Lineages 
Genome Biology and Evolution  2014;6(9):2361-2367.
Translation elongation factor-1 alpha (EF1A) and the related GTPase EF-like (EFL) are two proteins with a complex mutually exclusive distribution across the tree of eukaryotes. Recent surveys revealed that the distribution of the two GTPases in even closely related taxa is frequently at odds with their phylogenetic relationships. Here, we investigate the distribution of EF1A and EFL in the alveolate supergroup. Alveolates comprise three major lineages: ciliates and apicomplexans encode EF1A, whereas dinoflagellates encode EFL. We searched transcriptome databases for seven early-diverging alveolate taxa that do not belong to any of these groups: colpodellids, chromerids, and colponemids. Current data suggest all seven are expected to encode EF1A, but we find three genera encode EFL: Colpodella, Voromonas, and the photosynthetic Chromera. Comparing this distribution with the phylogeny of alveolates suggests that EF1A and EFL evolution in alveolates cannot be explained by a simple horizontal gene transfer event or lineage sorting.
doi:10.1093/gbe/evu186
PMCID: PMC4217694  PMID: 25179686
Elongation Factors; Alveolata; EF1A; EFL; Colpodellids; Chromerids; Colponemids
6.  Evidence for the Retention of Two Evolutionary Distinct Plastids in Dinoflagellates with Diatom Endosymbionts 
Genome Biology and Evolution  2014;6(9):2321-2334.
Dinoflagellates harboring diatom endosymbionts (termed “dinotoms”) have undergone a process often referred to as “tertiary endosymbiosis”—the uptake of algae containing secondary plastids and integration of those plastids into the new host. In contrast to other tertiary plastids, and most secondary plastids, the endosymbiont of dinotoms is distinctly less reduced, retaining a number of cellular features, such as their nucleus and mitochondria and others, in addition to their plastid. This has resulted in redundancy between host and endosymbiont, at least between some mitochondrial and cytosolic metabolism, where this has been investigated. The question of plastidial redundancy is particularly interesting as the fate of the host dinoflagellate plastid is unclear. The host cytosol possesses an eyespot that has been postulated to be a remnant of the ancestral peridinin plastid, but this has not been tested, nor has its possible retention of plastid functions. To investigate this possibility, we searched for plastid-associated pathways and functions in transcriptomic data sets from three dinotom species. We show that the dinoflagellate host has indeed retained genes for plastid-associated pathways and that these genes encode targeting peptides similar to those of other dinoflagellate plastid-targeted proteins. Moreover, we also identified one gene encoding an essential component of the dinoflagellate plastid protein import machinery, altogether suggesting the presence of a functioning plastid import system in the host, and by extension a relict plastid. The presence of the same plastid-associated pathways in the endosymbiont also extends the known functional redundancy in dinotoms, further confirming the unusual state of plastid integration in this group of dinoflagellates.
doi:10.1093/gbe/evu182
PMCID: PMC4217693  PMID: 25172904
tertiary endosymbiosis; dinotom; relict plastid; redundancy
7.  Endosymbiotic Gene Transfer in Tertiary Plastid-Containing Dinoflagellates 
Eukaryotic Cell  2014;13(2):246-255.
Plastid establishment involves the transfer of endosymbiotic genes to the host nucleus, a process known as endosymbiotic gene transfer (EGT). Large amounts of EGT have been shown in several photosynthetic lineages but also in present-day plastid-lacking organisms, supporting the notion that endosymbiotic genes leave a substantial genetic footprint in the host nucleus. Yet the extent of this genetic relocation remains debated, largely because the long period that has passed since most plastids originated has erased many of the clues to how this process unfolded. Among the dinoflagellates, however, the ancestral peridinin-containing plastid has been replaced by tertiary plastids on several more recent occasions, giving us a less ancient window to examine plastid origins. In this study, we evaluated the endosymbiotic contribution to the host genome in two dinoflagellate lineages with tertiary plastids. We generated the first nuclear transcriptome data sets for the “dinotoms,” which harbor diatom-derived plastids, and analyzed these data in combination with the available transcriptomes for kareniaceans, which harbor haptophyte-derived plastids. We found low level of detectable EGT in both dinoflagellate lineages, with only 9 genes and 90 genes of possible tertiary endosymbiotic origin in dinotoms and kareniaceans, respectively, suggesting that tertiary endosymbioses did not heavily impact the host dinoflagellate genomes.
doi:10.1128/EC.00299-13
PMCID: PMC3910982  PMID: 24297445
8.  The Marine Microbial Eukaryote Transcriptome Sequencing Project (MMETSP): Illuminating the Functional Diversity of Eukaryotic Life in the Oceans through Transcriptome Sequencing 
Keeling, Patrick J. | Burki, Fabien | Wilcox, Heather M. | Allam, Bassem | Allen, Eric E. | Amaral-Zettler, Linda A. | Armbrust, E. Virginia | Archibald, John M. | Bharti, Arvind K. | Bell, Callum J. | Beszteri, Bank | Bidle, Kay D. | Cameron, Connor T. | Campbell, Lisa | Caron, David A. | Cattolico, Rose Ann | Collier, Jackie L. | Coyne, Kathryn | Davy, Simon K. | Deschamps, Phillipe | Dyhrman, Sonya T. | Edvardsen, Bente | Gates, Ruth D. | Gobler, Christopher J. | Greenwood, Spencer J. | Guida, Stephanie M. | Jacobi, Jennifer L. | Jakobsen, Kjetill S. | James, Erick R. | Jenkins, Bethany | John, Uwe | Johnson, Matthew D. | Juhl, Andrew R. | Kamp, Anja | Katz, Laura A. | Kiene, Ronald | Kudryavtsev, Alexander | Leander, Brian S. | Lin, Senjie | Lovejoy, Connie | Lynn, Denis | Marchetti, Adrian | McManus, George | Nedelcu, Aurora M. | Menden-Deuer, Susanne | Miceli, Cristina | Mock, Thomas | Montresor, Marina | Moran, Mary Ann | Murray, Shauna | Nadathur, Govind | Nagai, Satoshi | Ngam, Peter B. | Palenik, Brian | Pawlowski, Jan | Petroni, Giulio | Piganeau, Gwenael | Posewitz, Matthew C. | Rengefors, Karin | Romano, Giovanna | Rumpho, Mary E. | Rynearson, Tatiana | Schilling, Kelly B. | Schroeder, Declan C. | Simpson, Alastair G. B. | Slamovits, Claudio H. | Smith, David R. | Smith, G. Jason | Smith, Sarah R. | Sosik, Heidi M. | Stief, Peter | Theriot, Edward | Twary, Scott N. | Umale, Pooja E. | Vaulot, Daniel | Wawrik, Boris | Wheeler, Glen L. | Wilson, William H. | Xu, Yan | Zingone, Adriana | Worden, Alexandra Z.
PLoS Biology  2014;12(6):e1001889.
Current sampling of genomic sequence data from eukaryotes is relatively poor, biased, and inadequate to address important questions about their biology, evolution, and ecology; this Community Page describes a resource of 700 transcriptomes from marine microbial eukaryotes to help understand their role in the world's oceans.
doi:10.1371/journal.pbio.1001889
PMCID: PMC4068987  PMID: 24959919
9.  Stabilizing the endothelium of donor hearts with fusogenic liposomes reduces myocardial injury and dysfunction 
The Journal of surgical research  2012;182(2):331-338.
Background
Myocardial injury after heart transplantation is a consequence of pathophysiological events initiated by local ischemia/reperfusion (IR) injury that is further aggravated by the inflammatory response due to blood exposure to the pump’s artificial surfaces during cardiopulmonary bypass (CPB). The purpose of this study was to determine the effectiveness of fusogenic lipid vesicles (FLVs) in enhancing the cardioprotective effect of St. Thomas organ preservation solution (ST). We hypothesized that donor hearts preserved with ST-FLVs will stabilize the endothelium during reperfusion, which in turn will reduce both endothelial barrier dysfunction and myocardial damage.
Materials and methods
To examine the effect of ST-FLVs therapy in vitro, C3b deposition and adhesion molecule expression studies were performed on human umbilical vein endothelial cells (HUVECs) challenged with plastic-contact-activated plasma. To assess the therapy in vivo, a cervical heterotopic working heart transplantation model in rats was used. Donor hearts were preserved for 1 h at 27°C (15min) and 4°C (45min), and after transplant were followed for 2 h. Left ventricular (LV) function and blood cardiac troponin I (cTnI) levels were quantified.
Results
HUVECs treated with ST-FLVs had reduced C3b deposition and expression of adhesion molecules compared to ST alone (P<0.05). Donor hearts receiving ST-FLVs therapy had reduced LV dysfunction and cTnI compared to ST alone
Conclusion
We conclude that FLVs enhance the cardioprotective effect of ST and reduce post-ischemic LV dysfunction and myocardial damage. The mechanism of protection appears to be associated with the stabilization of endothelial cell membranes due to incorporation of FLV-derived lipids.
doi:10.1016/j.jss.2012.10.022
PMCID: PMC3619012  PMID: 23140789
Ischemia-reperfusion injury; complement; transplantation; heart; liposomes; endothelium; rat
10.  Effects of Automated Immunization Registry Reporting via an Electronic Health Record Deployed in Community Practice Settings 
Applied Clinical Informatics  2013;4(2):267-275.
Background
Among the expected benefits of electronic health records (EHRs) is increased reporting of public health information, such as immunization status. State and local immunization registries aid control of vaccine-preventable diseases and help offset fragmentation in healthcare, but reporting is often slow and incomplete. The Primary Care Information Project (PCIP), an initiative of the NYC Department of Health and Mental Hygiene, has implemented EHRs with immunization reporting capability in community settings.
Objective and Methods
To evaluate the effect of automated reporting via an EHR on use and efficiency of reporting to the NY Citywide Immunization Registry, we conducted a secondary analysis of 1.7 million de-identified records submitted between January 2007 and June 2011 by 217 primary care practices enrolled in PCIP, pre and post launch of automated reporting via an EHR. We examined differences in records submitted per day, lag time, and documentation of eligibility for subsidized vaccines.
Results
Mean submissions per day did not change. Automated submissions of new and historical records increased by 18% and 98% respectively. Submissions within 14 days increased from 84% to 87%, and within 2 days increased from 60% to 77%. Median lag time decreased from 13 to 10 days. Documentation of eligibility decreased. Results are significant at p<0.001.
Conclusions
Significant improvements in registry use and efficiency of reporting were found after launch of automated reporting via an EHR. A decrease in eligibility documentation was attributed to EHR workflow. The limitations to comprehensive evaluation found in these data, which were extracted from a registry initiated prior to widespread EHR implementation suggests that reliable evaluation of immunization reporting via the EHR may require modifications to legacy registry databases.
doi:10.4338/ACI-2013-02-CR-0009
PMCID: PMC3716417  PMID: 23874363
Public health; electronic health records; immunization; health information exchange
11.  Proximal Superficial Femoral Artery Occlusion, Collateral Vessels, and Walking Performance in Peripheral Artery Disease 
JACC. Cardiovascular imaging  2013;6(6):687-694.
Objective
We studied associations of MRI-measured SFA occlusions with functional performance, leg symptoms, and collateral vessel number in PAD. We studied associations of collateral vessel number with functional performance in PAD.
Background
Associations of magnetic resonance imaging (MRI)-detected superficial femoral artery (SFA) occlusion and collateral vessel number with functional performance among individuals with peripheral artery disease (PAD) have not been reported.
Methods
457 participants with an ankle brachial index (ABI) < 1.00 had MRI measurement of the proximal SFA with twelve consecutive 2.5 millimeter cross-sectional images. An occluded SFA was defined as an SFA in which at least one segment was occluded. A non-occluded SFA was defined as absence of any occluded slices. Collateral vessels were visualized with magnetic resonance angiography (MRA). Lower extremity functional performance was measured with the six-minute walk, four-meter walking velocity at usual and fastest pace, and the short physical performance battery (SPPB) (0-12 scale, 12=best).
Results
Adjusting for age, sex, race, comorbidities, and other confounders, the presence of an SFA occlusion was associated with poorer six-minute walk performance (1,031 vs. 1,169 feet, P=0.006), slower fast-paced walking velocity (1.15 vs. 1.22 meters/second, P =0.042), and lower SPPB score (9.07 vs. 9.75, P=0.038) compared to the absence of an SFA occlusion. More numerous collateral vessels were associated with better six-minute walk performance (0-3 collaterals-1,064 feet, 4-7 collaterals-1,165 feet, ≥ 8 collaterals-1,246 feet, P trend=0.007), faster usual-paced walking speed (0-3 collaterals-0.84 meters/second, 4-7 collaterals-0.88 meters/second, ≥ 8 collaterals-0.91 meters/second, P trend=0.029), and faster rapid-paced walking speed (0-3 collaterals-1.17 meters/second, 4-7 collaterals-1.22 meters/second, ≥ 8 collaterals-1.29 meters/second, P trend=0.002), adjusting for age, sex, race, comorbidities, ABI, and other confounders.
Conclusions
Among PAD participants, MRI-visualized occlusions in the proximal SFA are associated with poorer functional performance, while more numerous collaterals are associated with better functional performance.
Clinical Trial ID
NCT00520412
doi:10.1016/j.jcmg.2012.10.024
PMCID: PMC3766720  PMID: 23647796
atherosclerotic plaque; intermittent claudication; peripheral arterial disease; physical functioning
12.  A Lack of Parasitic Reduction in the Obligate Parasitic Green Alga Helicosporidium 
PLoS Genetics  2014;10(5):e1004355.
The evolution of an obligate parasitic lifestyle is often associated with genomic reduction, in particular with the loss of functions associated with increasing host-dependence. This is evident in many parasites, but perhaps the most extreme transitions are from free-living autotrophic algae to obligate parasites. The best-known examples of this are the apicomplexans such as Plasmodium, which evolved from algae with red secondary plastids. However, an analogous transition also took place independently in the Helicosporidia, where an obligate parasite of animals with an intracellular infection mechanism evolved from algae with green primary plastids. We characterised the nuclear genome of Helicosporidium to compare its transition to parasitism with that of apicomplexans. The Helicosporidium genome is small and compact, even by comparison with the relatively small genomes of the closely related green algae Chlorella and Coccomyxa, but at the functional level we find almost no evidence for reduction. Nearly all ancestral metabolic functions are retained, with the single major exception of photosynthesis, and even here reduction is not complete. The great majority of genes for light-harvesting complexes, photosystems, and pigment biosynthesis have been lost, but those for other photosynthesis-related functions, such as Calvin cycle, are retained. Rather than loss of whole function categories, the predominant reductive force in the Helicosporidium genome is a contraction of gene family complexity, but even here most losses affect families associated with genome maintenance and expression, not functions associated with host-dependence. Other gene families appear to have expanded in response to parasitism, in particular chitinases, including those predicted to digest the chitinous barriers of the insect host or remodel the cell wall of Helicosporidium. Overall, the Helicosporidium genome presents a fascinating picture of the early stages of a transition from free-living autotroph to parasitic heterotroph where host-independence has been unexpectedly preserved.
Author Summary
Helicosporidium is a highly-adapted obligate parasite of animals. Its evolutionary origins were unclear for almost a century, but molecular analysis ultimately and surprisingly showed that it is a green alga, which means it has undergone an evolutionary transition from autotrophy to parasitism comparable to that of the malaria parasite Plasmodium and its relatives. Such transitions are often associated with the loss of biological functions that are no longer necessary in their novel environment and with the development of molecular mechanisms, sometimes quite sophisticated, to invade and take advantage of their hosts. Yet, very little is actually known about the early stages of the transition of a free-living organism to an obligate intracellular parasite. Here we sequenced the genome and transcriptome of Helicosporidium, and use it to show that the outcome of this transition is quite different from that of Plasmodium.
doi:10.1371/journal.pgen.1004355
PMCID: PMC4014436  PMID: 24809511
13.  Automated macro-vessel artifact correction in dynamic susceptibility magnetic resonance imaging using independent component analysis 
Dynamic susceptibility contrast (DSC) MRI is the most commonly used functional MRI-based method for studying changes in cerebral perfusion. However, several studies indicated a systematic overestimation of perfusion parameters compared to other imaging modalities related to the high sensitivity of DSC-MRI for blood flow in large vessels. In this study, we therefore suggest an improved, automated, robust and efficient method allowing for generating hemodynamic parameter maps where signal influence from large vessels is minimized. Based on independent component analysis (ICA), this fully automated approach corrects DSC-MRI data without any user interaction, thus making a clinical applicability possible. The accuracy of the proposed method was tested in ten patients with cerebrovascular disease. Application of our correction algorithm resulted in a significant reduction of the effect of macro-vessel signal on hemodynamic parameters like the cerebral blood flow (CBF) and the cerebral blood volume (CBV) compared to uncorrected data. As desired, our method specifically corrected for macro-vessel artifacts in cortical grey matter tissue, leaving white matter tissue parameters largely unaffected. This may increase sensitivity and reliability of detecting perfusion abnormalities in patient groups, in particular with regard to stroke and other cerebrovascular disorders.
doi:10.1002/mrm.22660
PMCID: PMC4003785  PMID: 20928868
Perfusion weighted MRI; Independent component analysis; Bolus tracking; Cerebral blood flow; Cerebral blood volume
14.  How the Mountain Pine Beetle (Dendroctonus ponderosae) Breached the Canadian Rocky Mountains 
Molecular Biology and Evolution  2014;31(7):1803-1815.
The mountain pine beetle (MPB; Dendroctonus ponderosae Hopkins), a major pine forest pest native to western North America, has extended its range north and eastward during an ongoing outbreak. Determining how the MPB has expanded its range to breach putative barriers, whether physical (nonforested prairie and high elevation of the Rocky Mountains) or climatic (extreme continental climate where temperatures can be below −40 °C), may contribute to our general understanding of range changes as well as management of the current epidemic. Here, we use a panel of 1,536 single nucleotide polymorphisms (SNPs) to assess population genetic structure, connectivity, and signals of selection within this MPB range expansion. Biallelic SNPs in MPB from southwestern Canada revealed higher genetic differentiation and lower genetic connectivity than in the northern part of its range. A total of 208 unique SNPs were identified using different outlier detection tests, of which 32 returned annotations for products with putative functions in cholesterol synthesis, actin filament contraction, and membrane transport. We suggest that MPB has been able to spread beyond its previous range by adjusting its cellular and metabolic functions, with genome scale differentiation enabling populations to better withstand cooler climates and facilitate longer dispersal distances. Our study is the first to assess landscape-wide selective adaptation in an insect. We have shown that interrogation of genomic resources can identify shifts in genetic diversity and putative adaptive signals in this forest pest species.
doi:10.1093/molbev/msu135
PMCID: PMC4069619  PMID: 24803641
structure; connectivity; dispersal; population genetics; outlier detection
15.  Description of Colponema vietnamica sp.n. and Acavomonas peruviana n. gen. n. sp., Two New Alveolate Phyla (Colponemidia nom. nov. and Acavomonidia nom. nov.) and Their Contributions to Reconstructing the Ancestral State of Alveolates and Eukaryotes 
PLoS ONE  2014;9(4):e95467.
The evolutionary and ecological importance of predatory flagellates are too often overlooked. This is not only a gap in our understanding of microbial diversity, but also impacts how we interpret their better-studied relatives. A prime example of these problems is found in the alveolates. All well-studied species belong to three large clades (apicomplexans, dinoflagellates, and ciliates), but the predatory colponemid flagellates are also alveolates that are rare in nature and seldom cultured, but potentially important to our understanding of alveolate evolution. Recently we reported the first cultivation and molecular analysis of several colponemid-like organisms representing two novel clades in molecular trees. Here we provide ultrastructural analysis and formal species descriptions for both new species, Colponema vietnamica n. sp. and Acavomonas peruviana n. gen. n. sp. Morphological and feeding characteristics concur with molecular data that both species are distinct members of alveolates, with Acavomonas lacking the longitudinal phagocytotic groove, a defining feature of Colponema. Based on ultrastructure and molecular phylogenies, which both provide concrete rationale for a taxonomic reclassification of Alveolata, we establish the new phyla Colponemidia nom. nov. for the genus Colponema and its close relatives, and Acavomonidia nom. nov. for the genus Acavomonas and its close relatives. The morphological data presented here suggests that colponemids are central to our understanding of early alveolate evolution, and suggest they also retain features of the common ancestor of all eukaryotes.
doi:10.1371/journal.pone.0095467
PMCID: PMC3989336  PMID: 24740116
16.  Revision of the theory of tracer transport and the convolution model of dynamic contrast enhanced magnetic resonance imaging 
Journal of mathematical biology  2007;55(3):389-411.
Counterexamples are used to motivate the revision of the established theory of tracer transport. Then dynamic contrast enhanced magnetic resonance imaging in particular is conceptualized in terms of a fully distributed convection–diffusion model from which a widely used convolution model is derived using, alternatively, compartmental discretizations or semigroup theory. On this basis, applications and limitations of the convolution model are identified. For instance, it is proved that perfusion and tissue exchange states cannot be identified on the basis of a single convolution equation alone. Yet under certain assumptions, particularly that flux is purely convective at the boundary of a tissue region, physiological parameters such as mean transit time, effective volume fraction, and volumetric flow rate per unit tissue volume can be deduced from the kernel.
doi:10.1007/s00285-007-0089-3
PMCID: PMC3986025  PMID: 17429633
Convection; Diffusion; Perfusion; Permeation; Tracer; Transport; DCE-MRI; Convolution; Nonidentifiability
17.  Draft genome of the mountain pine beetle, Dendroctonus ponderosae Hopkins, a major forest pest 
Genome Biology  2013;14(3):R27.
Background
The mountain pine beetle, Dendroctonus ponderosae Hopkins, is the most serious insect pest of western North American pine forests. A recent outbreak destroyed more than 15 million hectares of pine forests, with major environmental effects on forest health, and economic effects on the forest industry. The outbreak has in part been driven by climate change, and will contribute to increased carbon emissions through decaying forests.
Results
We developed a genome sequence resource for the mountain pine beetle to better understand the unique aspects of this insect's biology. A draft de novo genome sequence was assembled from paired-end, short-read sequences from an individual field-collected male pupa, and scaffolded using mate-paired, short-read genomic sequences from pooled field-collected pupae, paired-end short-insert whole-transcriptome shotgun sequencing reads of mRNA from adult beetle tissues, and paired-end Sanger EST sequences from various life stages. We describe the cytochrome P450, glutathione S-transferase, and plant cell wall-degrading enzyme gene families important to the survival of the mountain pine beetle in its harsh and nutrient-poor host environment, and examine genome-wide single-nucleotide polymorphism variation. A horizontally transferred bacterial sucrose-6-phosphate hydrolase was evident in the genome, and its tissue-specific transcription suggests a functional role for this beetle.
Conclusions
Despite Coleoptera being the largest insect order with over 400,000 described species, including many agricultural and forest pest species, this is only the second genome sequence reported in Coleoptera, and will provide an important resource for the Curculionoidea and other insects.
doi:10.1186/gb-2013-14-3-r27
PMCID: PMC4053930  PMID: 23537049
Coleoptera; Curculionoidea; Scolytinae; bark beetles; conifer; cytochrome P450; glutathione S-transferase; plant cell wall-degrading enzymes; horizontal gene transfer; sex chromosomes
18.  The Impact of Movements and Animal Density on Continental Scale Cattle Disease Outbreaks in the United States 
PLoS ONE  2014;9(3):e91724.
Globalization has increased the potential for the introduction and spread of novel pathogens over large spatial scales necessitating continental-scale disease models to guide emergency preparedness. Livestock disease spread models, such as those for the 2001 foot-and-mouth disease (FMD) epidemic in the United Kingdom, represent some of the best case studies of large-scale disease spread. However, generalization of these models to explore disease outcomes in other systems, such as the United States’s cattle industry, has been hampered by differences in system size and complexity and the absence of suitable livestock movement data. Here, a unique database of US cattle shipments allows estimation of synthetic movement networks that inform a near-continental scale disease model of a potential FMD-like (i.e., rapidly spreading) epidemic in US cattle. The largest epidemics may affect over one-third of the US and 120,000 cattle premises, but cattle movement restrictions from infected counties, as opposed to national movement moratoriums, are found to effectively contain outbreaks. Slow detection or weak compliance may necessitate more severe state-level bans for similar control. Such results highlight the role of large-scale disease models in emergency preparedness, particularly for systems lacking comprehensive movement and outbreak data, and the need to rapidly implement multi-scale contingency plans during a potential US outbreak.
doi:10.1371/journal.pone.0091724
PMCID: PMC3966763  PMID: 24670977
19.  Analysis of EST data of the marine protist Oxyrrhis marina, an emerging model for alveolate biology and evolution 
BMC Genomics  2014;15:122.
Background
The alveolates include a large number of important lineages of protists and algae, among which are three major eukaryotic groups: ciliates, apicomplexans and dinoflagellates. Collectively alveolates are present in virtually every environment and include a vast diversity of cell shapes, molecular and cellular features and feeding modes including lifestyles such as phototrophy, phagotrophy/predation and intracellular parasitism, in addition to a variety of symbiotic associations. Oxyrrhis marina is a well-known model for heterotrophic protist biology, and is now emerging as a useful organism to explore the many changes that occurred during the origin and diversification of dinoflagellates by virtue of its phylogenetic position at the base of the dinoflagellate tree.
Results
We have generated and analysed expressed sequence tag (EST) sequences from the alveolate Oxyrrhis marina in order to shed light on the evolution of a number of dinoflagellate characteristics, especially regarding the emergence of highly unusual genomic features. We found that O. marina harbours extensive gene redundancy, indicating high rates of gene duplication and transcription from multiple genomic loci. In addition, we observed a correlation between expression level and copy number in several genes, suggesting that copy number may contribute to determining transcript levels for some genes. Finally, we analyze the genes and predicted products of the recently discovered Dinoflagellate Viral Nuclear Protein, and several cases of horizontally acquired genes.
Conclusion
The dataset presented here has proven very valuable for studying this important group of protists. Our analysis indicates that gene redundancy is a pervasive feature of dinoflagellate genomes, thus the mechanisms involved in its generation must have arisen early in the evolution of the group.
doi:10.1186/1471-2164-15-122
PMCID: PMC3942190  PMID: 24512041
Dinoflagellates; Alveolates; Chromatin; Genome; Oxyrrhis
20.  Environmental distribution of coral-associated relatives of apicomplexan parasites 
The ISME Journal  2012;7(2):444-447.
A lineage of plastid-bearing eukaryotic microbes that is closely related to apicomplexan parasites was recently found in a specific association with coral reefs (apicomplexan-related lineage-V, or ARL-V). Here, we address the possible nature of this association using plastid ‘contamination' in fine-scale bacterial sequence surveys. In a transect between corals and associated macroalgae, ARL-V is specifically associated with the coral, in contrast to all microalgal types (including diatoms, haptophytes, pelagophytes and photosynthetic apicomplexan relatives, Chromera and Vitrella), which are associated with macroalgae. ARL-V is associated with at least 20 species of symbiotic corals through extended time periods and large geographic distances. It is significantly enriched in healthy coral tissue and shallow reef depths. Altogether, the evidence points to a specific relationship between ARL-V and corals, and is suggestive of symbiosis, perhaps based on photosynthesis.
doi:10.1038/ismej.2012.129
PMCID: PMC3554414  PMID: 23151646
apicomplexan-related lineages; Chromera; coral symbionts; coral reef ecosystem
21.  Horizontal Gene Transfer and Redundancy of Tryptophan Biosynthetic Enzymes in Dinotoms 
Genome Biology and Evolution  2014;6(2):333-343.
A tertiary endosymbiosis between a dinoflagellate host and diatom endosymbiont gave rise to “dinotoms,” cells with a unique nuclear and mitochondrial redundancy derived from two evolutionarily distinct eukaryotic lineages. To examine how this unique redundancy might have affected the evolution of metabolic systems, we investigated the transcription of genes involved in biosynthesis of the amino acid tryptophan in three species, Durinskia baltica, Kryptoperidinium foliaceum, and Glenodinium foliaceum. From transcriptome sequence data, we recovered two distinct sets of protein-coding transcripts covering the entire tryptophan biosynthetic pathway. Phylogenetic analyses suggest a diatom origin for one set of the proteins, which we infer to be expressed in the endosymbiont, and that the other arose from multiple horizontal gene transfer events to the dinoflagellate ancestor of the host lineage. This is the first indication that these cells retain redundant sets of transcripts and likely metabolic pathways for the biosynthesis of small molecules and extend their redundancy to their two distinct nuclear genomes.
doi:10.1093/gbe/evu014
PMCID: PMC3942023  PMID: 24448981
tryptophan biosynthesis; dinotoms; tertiary endosymbiosis; biochemical redundancy; dinoflagellates; diatoms
22.  The 3D Structure of the Apical Complex and Association with the Flagellar Apparatus Revealed by Serial TEM Tomography in Psammosa pacifica, a Distant Relative of the Apicomplexa 
PLoS ONE  2014;9(1):e84653.
The apical complex is one of the defining features of apicomplexan parasites, including the malaria parasite Plasmodium, where it mediates host penetration and invasion. The apical complex is also known in a few related lineages, including several non-parasitic heterotrophs, where it mediates feeding behaviour. The origin of the apical complex is unclear, and one reason for this is that in apicomplexans it exists in only part of the life cycle, and never simultaneously with other major cytoskeletal structures like flagella and basal bodies. Here, we used conventional TEM and serial TEM tomography to reconstruct the three dimensional structure of the apical complex in Psammosa pacifica, a predatory relative of apicomplexans and dinoflagellates that retains the archetype apical complex and the flagellar apparatus simultaneously. The P. pacifica apical complex is associated with the gullet and consists of the pseudoconoid, micronemes, and electron dense vesicles. The pseudoconoid is a convex sheet consisting of eight short microtubules, plus a band made up of microtubules that originate from the flagellar apparatus. The flagellar apparatus consists of three microtubular roots. One of the microtubular roots attached to the posterior basal body is connected to bypassing microtubular strands, which are themselves connected to the extension of the pseudoconoid. These complex connections where the apical complex is an extension of the flagellar apparatus, reflect the ancestral state of both, dating back to the common ancestor of apicaomplexans and dinoflagellates.
doi:10.1371/journal.pone.0084653
PMCID: PMC3879320  PMID: 24392150
23.  Fire in the Belly and the Professionalization of Nurses: A Historical Analysis of Crohn Disease Care 
Today professional nurses around the world are stepping up to meet the needs of individuals with Crohn disease using their specialized knowledge and skills that demonstrate areas of expertise that have not always existed. The gastrointestinal-specific knowledge being used by these 21st century nurses exists today because progressive efforts of nurses in previous decades moved the profession of nursing forward. The purpose of this paper is to describe and analyze the development of the role of nurses in responding to new challenges patients with Crohn disease face since the emergence of the disease in the early 1900s. The authors used traditional historic research methods to conduct the study. Primary sources include nursing journals and textbooks published in the 20th and 21st centuries and documents archived at The Mount Sinai Hospital in New York City, where Burrill B. Crohn conducted his seminal work. The significance of the findings is that the changing role of nurses in caring for patients with Crohn disease mirrors the professionalization of nursing during the 20th and early 21st centuries.
doi:10.1097/SGA.0b013e31827c5b8c
PMCID: PMC3581038  PMID: 23364362
25.  Modelling the spread of American foulbrood in honeybees 
We investigate the spread of American foulbrood (AFB), a disease caused by the bacterium Paenibacillus larvae, that affects bees and can be extremely damaging to beehives. Our dataset comes from an inspection period carried out during an AFB epidemic of honeybee colonies on the island of Jersey during the summer of 2010. The data include the number of hives of honeybees, location and owner of honeybee apiaries across the island. We use a spatial SIR model with an underlying owner network to simulate the epidemic and characterize the epidemic using a Markov chain Monte Carlo (MCMC) scheme to determine model parameters and infection times (including undetected ‘occult’ infections). Likely methods of infection spread can be inferred from the analysis, with both distance- and owner-based transmissions being found to contribute to the spread of AFB. The results of the MCMC are corroborated by simulating the epidemic using a stochastic SIR model, resulting in aggregate levels of infection that are comparable to the data. We use this stochastic SIR model to simulate the impact of different control strategies on controlling the epidemic. It is found that earlier inspections result in smaller epidemics and a higher likelihood of AFB extinction.
doi:10.1098/rsif.2013.0650
PMCID: PMC3785836  PMID: 24026473
epidemiology; Bayesian; MCMC; likelihood; honeybee; American foulbrood

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