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1.  Perceptions of Cardiovascular Health in an Underserved Community of Deaf Adults Using American Sign Language 
Disability and Health Journal  2011;4(3):192-197.
Cardiovascular disease leads in overall mortality and morbidity in the United States. Cardiovascular disparities remain high among minority and underserved groups. Deaf American Sign Language (ASL) users are an underserved and understudied group that receives little attention from researchers due to language and communication barriers. A recent ASL survey in Rochester, NY, indicated greater cardiovascular risk among Deaf participants.
To investigate risk perceptions of cardiovascular disease among Deaf ASL users, linking perceptions to features of Deaf culture and communication. This information will be used to inform future strategies to promote cardiovascular health among Deaf adults.
Methods and Participants
Four focus groups were conducted in Rochester, New York, with 22 Deaf participants in ASL. Videotaped sessions were translated and transcribed by a bilingual researcher. A team of investigators coded, analyzed and identified key themes from the data.
Main Results
Themes centered on five major domains: knowledge, barriers, facilitators, practices, and dissemination. The majority of themes focused on barriers and knowledge. Barriers included lack of health care information access due to language and communication challenges, financial constraints, and stress. Inconsistent knowledge emerged from many key areas of cardiovascular health.
The study outlines key themes for improving cardiovascular health knowledge and perceptions among Deaf ASL users. Findings suggest the importance of providing health educational programs and information in ASL to maximize understanding and minimize misconceptions. When caring for Deaf ASL users, providers should take extra effort to ask about cardiovascular risk factors and confirm patients’ understanding of these factors.
PMCID: PMC3378999  PMID: 21723526
ASL; Deaf; Deaf culture; cardiovascular health; risk perceptions
2.  Measurement of brain perfusion in newborns: Pulsed arterial spin labeling (PASL) versus pseudo-continuous arterial spin labeling (pCASL) 
NeuroImage : Clinical  2014;6:126-133.
Arterial spin labeling (ASL) perfusion-weighted imaging (PWI) by magnetic resonance imaging (MRI) has been shown to be useful for identifying asphyxiated newborns at risk of developing brain injury, whether or not therapeutic hypothermia was administered. However, this technique has been only rarely used in newborns until now, because of the challenges to obtain sufficient signal-to-noise ratio (SNR) and spatial resolution in newborns.
To compare two methods of ASL-PWI (i.e., single inversion-time pulsed arterial spin labeling [single TI PASL], and pseudo-continuous arterial spin labeling [pCASL]) to assess brain perfusion in asphyxiated newborns treated with therapeutic hypothermia and in healthy newborns.
We conducted a prospective cohort study of term asphyxiated newborns meeting the criteria for therapeutic hypothermia; four additional healthy term newborns were also included as controls. Each of the enrolled newborns was scanned at least once during the first month of life. Each MRI scan included conventional anatomical imaging, as well as PASL and pCASL PWI-MRI. Control and labeled images were registered separately to reduce the effect of motion artifacts. For each scan, the axial slice at the level of the basal ganglia was used for comparisons. Each scan was scored for its image quality. Quantification of whole-slice cerebral blood flow (CBF) was done afterwards using previously described formulas.
A total number of 61 concomitant PASL and pCASL scans were obtained in nineteen asphyxiated newborns treated with therapeutic hypothermia and four healthy newborns. After discarding the scans with very poor image quality, 75% (46/61) remained for comparison between the two ASL methods. pCASL images presented a significantly superior image quality score compared to PASL images (p < 0.0001). Strong correlation was found between the CBF measured by PASL and pCASL (r = 0.61, p < 0.0001).
This study demonstrates that both ASL methods are feasible to assess brain perfusion in healthy and sick newborns. However, pCASL might be a better choice over PASL in newborns, as pCASL perfusion maps had a superior image quality that allowed a more detailed identification of the different brain structures.
Graphical abstract
•Two methods of ASL-PWI were compared in newborns, i.e. PASL and pCASL.•Both methods are feasible to assess brain perfusion in newborns.•pCASL is a better choice over PASL in newborns.•pCASL perfusion maps had a superior image quality.
PMCID: PMC4215516  PMID: 25379424
Brain; Hypoxic–ischemic encephalopathy; Magnetic resonance imaging; Newborn; Perfusion; MRI, magnetic resonance imaging; PASL, pulsed arterial spin labeling; pCASL, pseudo-continuous arterial spin labeling; PWI, perfusion-weighted imaging; SNR, signal-to-noise ratio
3.  Optimized Simultaneous ASL and BOLD Functional Imaging of the Whole Brain 
To compare a double-excitation combined arterial-spin labeling/blood-oxygenation level dependent (ASL/BOLD) functional imaging method to a double-echo method. ASL provides a useful complement to standard BOLD functional imaging, to map effects of cerebral hemodynamics. Whole-brain imaging is necessary to properly characterize large functional networks. A challenge of whole-brain ASL/BOLD is that images for ASL functional contrast must be acquired before significant longitudinal relaxation of the inverted spins occurs; however a longer TE is required for optimal BOLD functional contrast, lengthening the acquisition time. Thus, existing combined ASL/BOLD studies have only partial-brain coverage.
Materials and Methods
The proposed method allows acquisition of images for ASL contrast within a short period after the ASL labeling pulse and post-inversion delay, then subsequent acquisition of images with longer TE for BOLD contrast. The technique is demonstrated using a narrative comprehension task in 35 normal children, and the double-excitation method is empirically compared to the double-echo method in 7 normal adults.
Compared to a double-echo sequence, simulations show the double-excitation method improves ASL contrast-to-noise ratio (CNR) (~50 %) in later-acquired slices with minimal (< 1 %) reduction in BOLD CNR in earlier-acquired slices if reduced excitation flip angles for the ASL acquisitions are used. Empirical results from adult data are in agreement with the simulations. Group analyses from the narrative comprehension task also show greater inter-subject sensitivity in BOLD versus ASL.
Our method simultaneously optimizes ASL and BOLD acquisitions for CNR while economizing acquisition time.
PMCID: PMC3964152  PMID: 24115454
Arterial Spin Labeling; BOLD functional imaging; pediatric neuroimaging
4.  Thymus Ontogeny in Frogs: T-Cell Renewal at Metamorphosis 
Developmental Immunology  1992;2(3):207-213.
Metamorphosis in amphibians presents a unique problem for the developing immune system. Because tadpoles are free-living, they need an immune system to protect against potential pathogens. However, at metamorphosis, they acquire a variety of new adultspecific molecules to which the tadpole immune system must become tolerant. We hypothesized that Xenopus laevis tadpoles may avoid potentially destructive antiself responses by largely discarding the larval immune system at metamorphosis and acquiring a new one. By implanting triploid (3N) thymuses into diploid (2N) hosts, we examined the influx and expansion of host T-cell precursors in the donor thymus of normally metamorphosing and metamorphosis-inhibited frogs. We observed that donor thymocytes are replaced by host-derived cells during metamorphosis, but inhibition of metamorphosis does not prevent this exchange of cells. The implanted thymuses export T cells to the spleen. This donor-derived pool of cells declines after metamorphosis in normally developing frogs but is retained to a greater extent if metamorphosis is inhibited. These studies confirm previous observations of a metamorphosis-associated wave of expansion of T cells and demonstrate that it is not dependent on the relatively high concentrations of thyroid hormones required for metamorphosis. Although some larval T cells persist through metamorphosis, others may be destroyed or the larval population is significantly diluted by the expanding adult population.
PMCID: PMC2275863  PMID: 1320967
Thymus ontogeny; Xenopus laevis; thyroid hormones; metamorphosis
The first specimen of Ammocoetes branchialis that showed histologically any atrophic changes in the endostyle was taken on July 16. These changes proceeded relatively rapidly for about a month, after which the endostyle as such was no longer recognized. All specimens examined after August 15 showed in cross section the characteristic ductless follicles more or less completely formed. More gradual and minor changes in the way of further absorption of cell remnants and completion of the follicles continued at least until September 1. Two specimens taken from the creek on September 4, 1911. showed complete follicle formation with some stainable colloid (figures 14 and 15). There was still yellow granular pigment in the fibrous tissue between the follicles. In two specimens taken on October 14, 1909, the pigment was absent and the follicles were more closely set, larger, and contained homogenous colloid. In the twenty-four specimens of ammocoetes studied, there were variations in the time of the onset of metamorphosis. There may also be variations in the rate of progress of the changes in different specimens. There is no evidence that removal of the animals from their native environment to the laboratory either increases or decreases the rate of metamorphosis. Schneider states that he was unable to get specimens kept in the laboratory to undergo metamorphosis. Gage, however, has repeatedly observed the metamorphosis under laboratory conditions, and the six of our specimens kept in the laboratory—some for forty days—remained in excellent condition and the metamorphosis proceeded as well as in those living in the creek. I know of no observations bearing on the question as to whether the metamorphosis may be hastened or delayed as it can be in tadpoles and other amphibia. It is probable, however, that physical conditions greatly influence the transformation. These observations as to the length of time from the inception to the completion of metamorphosis indicate that a month and probably longer is necessary for the lake and brook lampreys of Central New York. This is in agreement with the observations of Gage and of Muller on metamorphosis in general, but is at variance with the views of Bujor, who states that the process takes place within three to four days. The first endostylar changes are a gradual shrinkage in the whole organ with thickening of the capsule and septum and proliferation of the connective tissue in the periendostylar zone. The tongue anlage is developed in this thickening just dorsal to the endostyle and anterior to the gland orifice. The size of the chambers progressively decreases and with the thickening of the septum the halves of the endostyle are both absolutely and relatively more separated. All the five types of epithelia are affected, the first to show the change being type I, the four fan-shaped bundles of cuneiform cells of each half of the endostyle. These disappear totally quite early. The next type to show marked changes is type III, or the cells with yellow pigment granules. Here the change is progressive and these cell groups in different stages of atrophy may be traced through to the fully developed follicles. The epithelium of type V, or the endothelial-like lining of the parietal walls of the chambers, is piled up and extruded laterally as the chambers contract or shrink. These cells in different stages of atrophy may be followed until the metamorphosis is nearing completion. It is certain that the cells of types I, III, and V play no part in the formation of the ductless follicles. With types II and IV the question is not so easily settled as it is from one or the other or from both of these types that the permanent follicles arise. One can say definitely that type IV plays the major role, but whether the cells of type II after fusion with the basal group of type IV do not also share in the formation of the ventral follicle of the given chamber, I cannot decide, but from the evidence obtainable this seems probable. It is significant that the cells of type IV are continuous with, and indistinguishable from, the cells lining the orifice and are continued anteriorly in the deep pharyngeal groove and peripharyngeal grooves as well as posteriorally from the orifice in the small pharyngeal groove. As to the fate of this extraglandular epithelium of type IV I have no data save that with the closing of the orifice and the formation of the permanent branchial sac these grooves with their ciliated epithelium disappear and the whole sac comes to be lined with plain stratified epithelium. The fact that the cells of the pharyngeal grooves and the lining cells of the gland orifice are continuous with the cells of the endostyle from which the permanent thyroid follicles are formed is not without significance in relation to the development of the thyroid of the higher chordates. One or more very large follicles are formed from the lower portion of this orificial epithelium of type IV. Four ductless follicles are the maximum number that may be formed primarily in each half of the endostyle from the four areas of epithelium of type IV. From the specimens studied this maximum is frequently not obtained. Posterior to the orifice where four chambers exist, each corresponding to one half of an anterior chamber, but two follicles may be formed from each chamber, but in the coil these are proportionately increased, in cross section. Most of the detailed studies here recorded have been made on the part of the endostyle posterior to the coil where the simplest conditions exist. Here two follicles are ordinarily formed from each chamber. In cross sections the follicles are at first only long tubules whose cavities are the remnants of the original endostyle chambers, but when the metamorphosis is completed each of these primary tubules is cut up into several elongated closed sacs corresponding to the true ductless follicles of all higher chordates. New follicles also arise by budding from these primary ones, and this process is probably of normal occurrence at the metamorphosis.
PMCID: PMC2125049  PMID: 19867651
6.  The rice ALS3 encoding a novel pentatricopeptide repeat protein is required for chloroplast development and seedling growth 
Rice  2015;8:17.
Pentatricopeptide repeat (PPR) proteins play essential roles in modulating the expression of organelle genes and have expanded greatly in higher plants. However, molecular mechanisms of most rice PPR genes remain unclear.
In this study, a new rice PPR mutant, asl3 (albinoseedlinglethality3) exhibits an albino lethal phenotype at the seedling stage. This albino phenotype was associated with altered photosynthetic-pigment and chloroplast development. Map-based cloning showed that ASL3 encodes a novel rice PPR protein with 10 tandem PPR motifs, which localizes to the chloroplast. ASL3 showed tissue-specific expression, as it was highly expressed in the chlorenchyma, but expressed at much lower levels in roots and panicles. RNAi of ASL3 confirmed that ASL3 plays an essential role in the early development and chloroplast development in rice. Moreover, expression analysis revealed that the asl3 mutation severely affected the transcriptional levels of important genes associated with plastid translation machinery and photosynthesis, which may impair photosynthesis and finally led to the seedling death in asl3 mutant. These results evidenced the important role of ASL3 in the early development of rice, especially chloroplast development.
The ASL3 gene encoded a novel chloroplast-targeted PPR protein with 10 tandem PPR motifs in rice. Disruption of the ASL3 would lead to a defective chloroplast and seedling lethality, and affected expression levels of genes associated with chloroplast development and photosynthesis at early leaf stage of rice.
Electronic supplementary material
The online version of this article (doi:10.1186/s12284-015-0050-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4390607  PMID: 25859292
Albino; Chloroplast development; Lethality; Rice; Pentatricopeptide repeat (PPR) proteins
7.  Effect of thyroid hormone concentration on the transcriptional response underlying induced metamorphosis in the Mexican axolotl (Ambystoma) 
BMC Genomics  2008;9:78.
Thyroid hormones (TH) induce gene expression programs that orchestrate amphibian metamorphosis. In contrast to anurans, many salamanders do not undergo metamorphosis in nature. However, they can be induced to undergo metamorphosis via exposure to thyroxine (T4). We induced metamorphosis in juvenile Mexican axolotls (Ambystoma mexicanum) using 5 and 50 nM T4, collected epidermal tissue from the head at four time points (Days 0, 2, 12, 28), and used microarray analysis to quantify mRNA abundances.
Individuals reared in the higher T4 concentration initiated morphological and transcriptional changes earlier and completed metamorphosis by Day 28. In contrast, initiation of metamorphosis was delayed in the lower T4 concentration and none of the individuals completed metamorphosis by Day 28. We identified 402 genes that were statistically differentially expressed by ≥ two-fold between T4 treatments at one or more non-Day 0 sampling times. To complement this analysis, we used linear and quadratic regression to identify 542 and 709 genes that were differentially expressed by ≥ two-fold in the 5 and 50 nM T4 treatments, respectively.
We found that T4 concentration affected the timing of gene expression and the shape of temporal gene expression profiles. However, essentially all of the identified genes were similarly affected by 5 and 50 nM T4. We discuss genes and biological processes that appear to be common to salamander and anuran metamorphosis, and also highlight clear transcriptional differences. Our results show that gene expression in axolotls is diverse and precise, and that axolotls provide new insights about amphibian metamorphosis.
PMCID: PMC2262897  PMID: 18267027
8.  Combined Arterial Spin Label and Dynamic Susceptibility Contrast Measurement of Cerebral Blood Flow 
Dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) are both used to measure cerebral blood flow (CBF), but neither technique is ideal. Absolute DSC-CBF quantitation is challenging due to many uncertainties, including partial-volume errors and nonlinear contrast relaxivity. ASL can measure quantitative CBF in regions with rapidly arriving flow, but CBF is underestimated in regions with delayed arrival. To address both problems, we have derived a patient-specific correction factor, the ratio of ASL- and DSC-CBF, calculated only in short-arrival-time regions (as determined by the DSC-based normalized bolus arrival time [Tmax]). We have compared the combined CBF method to gold-standard xenon CT in 20 patients with cerebrovascular disease, using a range of Tmax threshold levels. Combined ASL and DSC CBF demonstrated quantitative accuracy as good as the ASL technique but with improved correlation in voxels with long Tmax. The ratio of MRI-based CBF to xenon CT CBF (coefficient of variation) was 90 ± 30% (33%) for combined ASL and DSC CBF, 43 ± 21% (47%) for DSC, and 91 ± 31% (34%) for ASL (Tmax threshold 3 sec). These findings suggest that combining ASL and DSC perfusion measurements improves quantitative CBF measurements in patients with cerebrovascular disease.
PMCID: PMC2905651  PMID: 20512858
magnetic resonance imaging; perfusion; computed tomography; xenon CT; cerebral blood flow; quantitative
9.  Measuring Airway Surface Liquid Depth in Ex Vivo Mouse Airways by X-Ray Imaging for the Assessment of Cystic Fibrosis Airway Therapies 
PLoS ONE  2013;8(1):e55822.
In the airways of those with cystic fibrosis (CF), the leading pathophysiological hypothesis is that an ion channel defect results in a relative decrease in airway surface liquid (ASL) volume, producing thick and sticky mucus that facilitates the establishment and progression of early fatal lung disease. This hypothesis predicts that any successful CF airway treatment for this fundamental channel defect should increase the ASL volume, but up until now there has been no method of measuring this volume that would be compatible with in vivo monitoring. In order to accurately monitor the volume of the ASL, we have developed a new x-ray phase contrast imaging method that utilizes a highly attenuating reference grid. In this study we used this imaging method to examine the effect of a current clinical CF treatment, aerosolized hypertonic saline, on ASL depth in ex vivo normal mouse tracheas, as the first step towards non-invasive in vivo ASL imaging. The ex vivo tracheas were treated with hypertonic saline, isotonic saline or no treatment using a nebuliser integrated within a small animal ventilator circuit. Those tracheas exposed to hypertonic saline showed a transient increase in the ASL depth, which continued for nine minutes post-treatment, before returning to baseline by twelve minutes. These findings are consistent with existing measurements on epithelial cell cultures, and therefore suggest promise for the future development of in vivo testing of treatments. Our grid-based imaging technique measures the ASL depth with micron resolution, and can directly observe the effect of treatments expected to increase ASL depth, prior to any changes in overall lung health. The ability to non-invasively observe micron changes in the airway surface, particularly if achieved in an in vivo setting, may have potential in pre-clinical research designed to bring new treatments for CF and other airway diseases to clinical trials.
PMCID: PMC3559635  PMID: 23383288
10.  Dependency on de novo protein synthesis and proteomic changes during metamorphosis of the marine bryozoan Bugula neritina 
Proteome Science  2010;8:25.
Metamorphosis in the bryozoan Bugula neritina (Linne) includes an initial phase of rapid morphological rearrangement followed by a gradual phase of morphogenesis. We hypothesized that the first phase may be independent of de novo synthesis of proteins and, instead, involves post-translational modifications of existing proteins, providing a simple mechanism to quickly initiate metamorphosis. To test our hypothesis, we challenged B. neritina larvae with transcription and translation inhibitors. Furthermore, we employed 2D gel electrophoresis to characterize changes in the phosphoproteome and proteome during early metamorphosis. Differentially expressed proteins were identified by liquid chromatography tandem mass spectrometry and their gene expression patterns were profiled using semi-quantitative real time PCR.
When larvae were incubated with transcription and translation inhibitors, metamorphosis initiated through the first phase but did not complete. We found a significant down-regulation of 60 protein spots and the percentage of phosphoprotein spots decreased from 15% in the larval stage to12% during early metamorphosis. Two proteins--the mitochondrial processing peptidase beta subunit and severin--were abundantly expressed and phosphorylated in the larval stage, but down-regulated during metamorphosis. MPPbeta and severin were also down-regulated on the gene expression level.
The initial morphogenetic changes that led to attachment of B. neritina did not depend on de novo protein synthesis, but the subsequent gradual morphogenesis did. This is the first time that the mitochondrial processing peptidase beta subunit or severin have been shown to be down-regulated on both gene and protein expression levels during the metamorphosis of B. neritina. Future studies employing immunohistochemistry to reveal the expression locality of these two proteins during metamorphosis should provide further evidence of the involvement of these two proteins in the morphogenetic rearrangement of B. neritina.
PMCID: PMC2890537  PMID: 20497544
INTED proceedings  2015;2015:7577-7584.
The University of Puerto Rico (UPR), Medical Sciences Campus (MSC) post-doctoral Master of Science in Clinical and Translational Research (MSc) program aims to train Hispanic post-doctoral candidates to advance their careers and become successful clinical and translational researchers geared to help eliminate health disparities. Its curriculum highlights the use of technology and online resources to maximize time use of time and efforts. As part of the assessment efforts, the program’s Evaluation Committee leads an annual activity, Evaluation Retreat (ER), to evaluate the program’s curriculum, research component, and mentoring experience according to Scholars’ perspective. Results are used by the Program Executive committee for further planning and improvement. This analysis presents the most relevant results from these activities.
Design Methods
Data collection (from last 5 years), include quantitative (online surveys) and qualitative approaches (a group meeting with Scholars.) Questionnaires request Scholars to rate specific features of the program’s research component, mentoring experience and curriculum. It also includes questions about the program in general (major strengths and challenges, and recommendations for improvement. During the group meeting, Scholars discuss these results and present consensus in a plenary session. Quantitative data are managed and analyzed using the statistical software SPSS. Qualitative data are examined using content analysis.
Scholars identified as program’s strengths the networking opportunities (local and with U.S. experts), the diversity of peers and faculty, the faculty support, the technical and audiovisual support, the physical facilities and resources, the guest speakers and consultants, and the quality of the curriculum. Challenges vary as cohorts change, but time limitations and the need for technical/statistical support are always highlighted. Recommendations for improvement emphasize the need for a greater pool of experienced mentors, and more hands-on approaches to address particular skills such as, manuscript development, institutional and federal guidelines for proposal submission, and issues related to the research project management.
Evaluation Retreats provide a valuable input to improve a program geared to develop competent clinical researchers. Findings evidence the program’s commitment with providing the foundation for an enhanced mass of clinical researchers.
PMCID: PMC4791064  PMID: 26985449
Assessment; research methods
12.  Supporting progress towards the post-2015 targets and regional tuberculosis elimination: a statement of intent from the third meeting of the Asian TB Experts Community 
The European Respiratory Journal  2015;45(6):1760-1762.
The World Health Organization (WHO) is challenging all countries, both high- and low-incidence, to dramatically intensify efforts to meet bold new goals of reducing global tuberculosis (TB) deaths by 95% and the incidence by 90% (<10 cases per 100 000 population) by 2035 [1]. This radical strategic change came from the recognition that the current strategy of passive case finding and directly observed therapy (DOT) is not sufficiently curbing the incidence of TB. The new strategy calls for a synergy of interventions to enable early case detection, systematic screening and prevention of TB in contacts (adults and children) and high-risk groups, such as people living with HIV or other immune depressing conditions, people with diabetes, patients receiving dialysis, patients preparing for organ or haematological transplantation, patients with silicosis, prisoners, healthcare workers, homeless individuals, illicit drug users and individuals in communal settings. At the end of 2014, the WHO released the first guidelines on the management of latent tuberculosis infection (LTBI). The guidelines provide evidence based guidance on practices for testing, treating and managing LTBI in infected individuals with the highest likelihood of progression to active disease [2]. Although primarily aimed at high-income or upper middle-income countries, with an estimated TB incidence rate of <100 per 100 000 population, they represent an unprecedented gear change in the scaling up of TB prevention as a component of TB control programmes [2].
In the first concerted Asian reaction to the post-2015 strategy the significance of TB screening was recognised
PMCID: PMC4450152  PMID: 26028624
13.  Engaging the Deaf American Sign Language Community: Lessons From a Community-Based Participatory Research Center 
Numerous publications demonstrate the importance of community-based participatory research (CBPR) in community health research, but few target the Deaf community. The Deaf community is understudied and underrepresented in health research despite suspected health disparities and communication barriers.
The goal of this paper is to share the lessons learned from the implementation of CBPR in an understudied community of Deaf American Sign Language (ASL) users in the greater Rochester, New York, area.
We review the process of CBPR in a Deaf ASL community and identify the lessons learned.
Key CBPR lessons include the importance of engaging and educating the community about research, ensuring that research benefits the community, using peer-based recruitment strategies, and sustaining community partnerships. These lessons informed subsequent research activities.
This report focuses on the use of CBPR principles in a Deaf ASL population; lessons learned can be applied to research with other challenging-to-reach populations.
PMCID: PMC3576694  PMID: 22982845
Community-based participatory research; health disparities; vulnerable populations; academic medical centers; health care facilities manpower and services; Deaf American Sign Language users
14.  Arterial Spin Labeling (ASL) fMRI: Advantages, Theoretical Constrains and Experimental Challenges in Neurosciences 
Cerebral blood flow (CBF) is a well-established correlate of brain function and therefore an essential parameter for studying the brain at both normal and diseased states. Arterial spin labeling (ASL) is a noninvasive fMRI technique that uses arterial water as an endogenous tracer to measure CBF. ASL provides reliable absolute quantification of CBF with higher spatial and temporal resolution than other techniques. And yet, the routine application of ASL has been somewhat limited. In this review, we start by highlighting theoretical complexities and technical challenges of ASL fMRI for basic and clinical research. While underscoring the main advantages of ASL versus other techniques such as BOLD, we also expound on inherent challenges and confounds in ASL perfusion imaging. In closing, we expound on several exciting developments in the field that we believe will make ASL reach its full potential in neuroscience research.
PMCID: PMC3432878  PMID: 22966219
15.  Fossil evidence for key innovations in the evolution of insect diversity 
Explaining the taxonomic richness of the insects, comprising over half of all described species, is a major challenge in evolutionary biology. Previously, several evolutionary novelties (key innovations) have been posited to contribute to that richness, including the insect bauplan, wings, wing folding and complete metamorphosis, but evidence over their relative importance and modes of action is sparse and equivocal. Here, a new dataset on the first and last occurrences of fossil hexapod (insects and close relatives) families is used to show that basal families of winged insects (Palaeoptera, e.g. dragonflies) show higher origination and extinction rates in the fossil record than basal wingless groups (Apterygota, e.g. silverfish). Origination and extinction rates were maintained at levels similar to Palaeoptera in the more derived Polyneoptera (e.g. cockroaches) and Paraneoptera (e.g. true bugs), but extinction rates subsequently reduced in the very rich group of insects with complete metamorphosis (Holometabola, e.g. beetles). Holometabola show evidence of a recent slow-down in their high net diversification rate, whereas other winged taxa continue to diversify at constant but low rates. These data suggest that wings and complete metamorphosis have had the most effect on family-level insect macroevolution, and point to specific mechanisms by which they have influenced insect diversity through time.
PMCID: PMC4173696  PMID: 25165766
adaptive radiation; extinction; flight; Hexapoda; macroevolution; complete metamorphosis
16.  Metamorphoses of Malaria: The role of autophagy in parasite differentiation 
Essays in biochemistry  2011;51:127-136.
Several protozoan parasites undergo a complex lifecycle that alternates between an invertebrate vector and a vertebrate host. Adaptations to these different environments by the parasites are achieved by drastic changes in their morphology and metabolism. The malaria parasites must be transmitted to a mammal from a mosquito as part of their lifecycle. Upon entering the mammalian host, extracellular malaria sporozoites reach the liver and invade hepatocytes, wherein they meet the challenge of becoming replication-competent schizonts. During the process of conversion, the sporozoite selectively discards organelles that are unnecessary for the parasite growth in liver cells. Among the organelles that are cleared from the sporozoite are the micronemes, abundant secretory vesicles that facilitates the adhesion of the parasite to hepatocytes. Organelles specialized in sporozoite motility and structure, such as the inner membrane complex (a major component of the motile parasite’s cytoskeleton), are also eliminated from converting parasites. The high degree of sophistication of the metamorphosis that occurs at the onset of the liver form development cascade suggests that the observed changes must be multifactorial. Among the mechanisms implicated in the elimination of sporozoite organelles, the degradative process called autophagy contributes to the remodeling of parasite interior and the production of replicative liver forms. In a broader context, the importance of the role played by autophagy during the differentiation of protozoan parasites that cycle between insects and vertebrates is nowadays clearly emerging. An exciting prospect derived from these observations is that the parasite proteins involved in the autophagic process may represent new targets for drug development.
PMCID: PMC4109265  PMID: 22023446
Protozoan parasites; Malaria; Plasmodium; Sporozoite; Lifecycle differentiation; Autophagy; Evolution; Drug discovery
17.  Developmental compartments in the larval trachea of Drosophila 
eLife  null;4:e08666.
The Drosophila tracheal system is a branched tubular network that forms in the embryo by a post-mitotic program of morphogenesis. In third instar larvae (L3), cells constituting the second tracheal metamere (Tr2) reenter the cell cycle. Clonal analysis of L3 Tr2 revealed that dividing cells in the dorsal trunk, dorsal branch and transverse connective branches respect lineage restriction boundaries near branch junctions. These boundaries corresponded to domains of gene expression, for example where cells expressing Spalt, Delta and Serrate in the dorsal trunk meet vein–expressing cells in the dorsal branch or transverse connective. Notch signaling was activated to one side of these borders and was required for the identity, specializations and segregation of border cells. These findings suggest that Tr2 is comprised of developmental compartments and that developmental compartments are an organizational feature relevant to branched tubular networks.
eLife digest
As a fruit fly develops, its cells may sort themselves into groups according to the type of cell that they will eventually become. Some groups form ‘developmental compartments’ that are separated by boundaries that cells cannot move across. All the descendants of a cell in a compartment will activate the same specific gene (called a ‘selector’ gene) that determines their identity and fate. Similar compartments also form in the developing hindbrains of mammals, but it is not clear how general this mechanism of tissue patterning is.
Fruit fly larvae undergo a physical transformation called metamorphosis to become adult fruit flies. Here, Rao et al. discover that the cells in the developing airways (or trachea) of the larvae at the start of metamorphosis are organised into compartments. At this stage the cells in the trachea start to divide and grow to make the adult tracheal system. The experiments show that these cells do not spread from one main branch of the tracheal system into another. Instead, the cells cluster in locations where the different branches meet on either side of a straight boundary.
The cells on each side of these boundaries activate different genes that regulate their identity and development. For example, cells in one branch of the system switch on a selector gene that makes a protein called Spalt. A pathway known as Notch signaling is activated by cells on the other side of a nearby boundary in a different branch of the tracheal system. This separation of Spalt production and Notch activation establishes a cell communication system that keeps the cells of the different compartments apart.
Rao et al.’s findings reveal a role for the Notch protein in regulating the organization of cells into compartments to form branches in fruit fly airways. A future challenge is to find out if Notch plays a similar role in other branched tissues, such as blood vessels.
PMCID: PMC4718809  PMID: 26491942
developmental compartments; trachea; notch; D. melanogaster
18.  Asterless Licenses Daughter Centrioles to Duplicate for the First Time in Drosophila Embryos 
Current Biology  2014;24(11):1276-1282.
Centrioles form centrosomes and cilia, and defects in any of these three organelles are associated with human disease [1]. Centrioles duplicate once per cell cycle, when a mother centriole assembles an adjacent daughter during S phase. Daughter centrioles cannot support the assembly of another daughter until they mature into mothers during the next cell cycle [2–5]. The molecular nature of this daughter-to-mother transition remains mysterious. Pioneering studies in C. elegans identified a set of core proteins essential for centriole duplication [6–12], and a similar set have now been identified in other species [10, 13–18]. The protein kinase ZYG-1/Sak/Plk4 recruits the inner centriole cartwheel components SAS-6 and SAS-5/Ana2/STIL, which then recruit SAS-4/CPAP, which in turn helps assemble the outer centriole microtubules [19, 20]. In flies and humans, the Asterless/Cep152 protein interacts with Sak/Plk4 and Sas-4/CPAP and is required for centriole duplication, although its precise role in the assembly pathway is unclear [21–24]. Here, we show that Asl is not incorporated into daughter centrioles as they assemble during S phase but is only incorporated once mother and daughter separate at the end of mitosis. The initial incorporation of Asterless (Asl) is irreversible, requires DSas-4, and, crucially, is essential for daughter centrioles to mature into mothers that can support centriole duplication. We therefore propose a “dual-licensing” model of centriole duplication, in which Asl incorporation provides a permanent primary license to allow new centrioles to duplicate for the first time, while centriole disengagement provides a reduplication license to allow mother centrioles to duplicate again.
Graphical Abstract
•Daughter centrioles do not incorporate Asterless during their assembly•New centrioles recruit Asl once they disengage from their mother centriole•The initial incorporation of Asl is irreversible and requires DSas-4•Asl incorporation is essential for disengaged new centrioles to duplicate
Novak et al. show that the key Drosophila centriole duplication protein Asterless is not incorporated into new centrioles as they assemble but is incorporated later once the centrioles disengage. Asl incorporation depends on DSas-4 and is essential for new centrioles to duplicate, suggesting a “dual-licensing” model of centriole duplication.
PMCID: PMC4046630  PMID: 24835456
19.  The effects of learning American Sign Language on co-speech gesture* 
Bilingualism (Cambridge, England)  2012;15(4):677-686.
Given that the linguistic articulators for sign language are also used to produce co-speech gesture, we examined whether one year of academic instruction in American Sign Language (ASL) impacts the rate and nature of gestures produced when speaking English. A survey study revealed that 75% of ASL learners (N = 95), but only 14% of Romance language learners (N = 203), felt that they gestured more after one year of language instruction. A longitudinal study confirmed this perception. Twenty-one ASL learners and 20 Romance language learners (French, Italian, Spanish) were filmed re-telling a cartoon story before and after one academic year of language instruction. Only the ASL learners exhibited an increase in gesture rate, an increase in the production of iconic gestures, and an increase in the number of handshape types exploited in co-speech gesture. Five ASL students also produced at least one ASL sign when re-telling the cartoon. We suggest that learning ASL may (i) lower the neural threshold for co-speech gesture production, (ii) pose a unique challenge for language control, and (iii) have the potential to improve cognitive processes that are linked to gesture.
PMCID: PMC3547625  PMID: 23335853
gesture; American Sign Language; bilingualism
20.  Assessing Health Literacy in Deaf American Sign Language Users 
Journal of health communication  2015;20(0 2):92-100.
Communication and language barriers isolate Deaf American Sign Language (ASL) users from mass media, healthcare messages, and health care communication, which when coupled with social marginalization, places them at a high risk for inadequate health literacy. Our objectives were to translate, adapt, and develop an accessible health literacy instrument in ASL and to assess the prevalence and correlates of inadequate health literacy among Deaf ASL users and hearing English speakers using a cross-sectional design. A total of 405 participants (166 Deaf and 239 hearing) were enrolled in the study. The Newest Vital Sign was adapted, translated, and developed into an ASL version of the NVS (ASL-NVS). Forty-eight percent of Deaf participants had inadequate health literacy, and Deaf individuals were 6.9 times more likely than hearing participants to have inadequate health literacy. The new ASL-NVS, available on a self-administered computer platform, demonstrated good correlation with reading literacy. The prevalence of Deaf ASL users with inadequate health literacy is substantial, warranting further interventions and research.
PMCID: PMC4714330  PMID: 26513036
21.  Comparing Kidney Perfusion Using Noncontrast Arterial Spin Labeling MRI and Microsphere Methods in an Interventional Swine Model 
Investigative Radiology  2011;46(2):124-131.
The purpose of this study was to assess the ability of a flow-sensitive alternating inversion recovery–arterial spin labeling (FAIR-ASL) technique to track renal perfusion changes during pharmacologic and physiologic alterations in renal blood flow using microspheres as a gold standard.
Materials and Methods
Fluorescent microsphere and FAIR-ASL perfusion were compared in the cortex of the kidney for 11 swine across 4 interventional time points: (1) under baseline conditions, (2) during an acetylcholine and fluid bolus challenge to increase perfusion, (3) initially after switching to isoflurane anesthesia, and (4) after 2 hours of isoflurane anesthesia. In 10 of the 11 swine, a bag of ice was placed on the hilum of 1 kidney at the beginning of isoflurane administration to further reduce perfusion in 1 kidney.
Both ASL and microspheres tracked the expected cortical perfusion changes (P < 0.02) across the interventions, including an increase in perfusion during the acetylcholine challenge and decrease during the administration of isoflurane. Both techniques also measured lower cortical perfusion in the iced compared with the noniced kidneys (P ≤ 0.01). The ASL values were systematically lower compared with microsphere perfusion. Very good correlation (r = 0.81, P < 0.0001) was observed between the techniques, and the relationship appeared linear for perfusion values in the expected physiologic range (microsphere perfusion <550 mL/min/100 g) although ASL values saturated for perfusion >550 mL/min/100 g.
Cortical perfusion measured with ASL correlated with microspheres and reliably detected changes in renal perfusion in response to physiologic challenge.
PMCID: PMC3368348  PMID: 22609830
kidney perfusion; MRI; arterial spin labeling; renal perfusion; swine; microspheres
22.  A mechanochemical model for auto-regulation of lung airway surface layer volume 
We develop a proof-of-principle model for auto-regulation of water volume in the lung airway surface layer (ASL) by coupling biochemical kinetics, transient ASL volume, and homeostatic mechanical stresses. The model is based on the hypothesis that ASL volume is sensed through soluble mediators and phasic stresses generated by beating cilia and air drag forces. Model parameters are fit based on available data on human bronchial epithelial cell cultures. Simulations then demonstrate that homeostatic volume regulation is a natural consequence of the processes described. The model maintains ASL volume within a physiological range that modulates with phasic stress frequency and amplitude. Next, we show that the model successfully reproduces the responses of cell cultures to significant isotonic and hypotonic challenges, and to hypertonic saline, an effective therapy for mucus hydration in cystic fibrosis patients. These results compel an advanced airway hydration model with therapeutic value that will necessitate detailed kinetics of multiple molecular pathways, feedback to ASL viscoelasticity properties, and stress signaling from the ASL to the cilia and epithelial cells.
PMCID: PMC3631568  PMID: 23415939
Volume regulation; mechanochemical mathematical model; respiratory epithelia; cilia; mucus; viscoelasticity
23.  Application of Arterial Spin Labelling in the Assessment of Ocular Tissues 
BioMed Research International  2016;2016:6240504.
Arterial spin labelling (ASL) is a noninvasive magnetic resonance imaging (MRI) modality, capable of measuring blood perfusion without the use of a contrast agent. While ASL implementation for imaging the brain and monitoring cerebral blood flow has been reviewed in depth, the technique is yet to be widely used for ocular tissue imaging. The human retina is a very thin but highly stratified structure and it is also situated close to the surface of the body which is not ideal for MR imaging. Hence, the application of MR imaging and ASL in particular has been very challenging for ocular tissues and retina. That is despite the fact that almost all of retinal pathologies are accompanied by blood perfusion irregularities. In this review article, we have focused on the technical aspects of the ASL and their implications for its optimum adaptation for retinal blood perfusion monitoring. Retinal blood perfusion has been assessed through qualitative or invasive quantitative methods but the prospect of imaging flow using ASL would increase monitoring and assessment of retinal pathologies. The review provides details of ASL application in human ocular blood flow assessment.
PMCID: PMC4811053  PMID: 27066501
24.  When does Iconicity in Sign Language Matter? 
Language and cognitive processes  2012;28(3):261-271.
We examined whether iconicity in American Sign Language (ASL) enhances translation performance for new learners and proficient signers. Fifteen hearing nonsigners and 15 proficient ASL-English bilinguals performed a translation recognition task and a production translation task. Nonsigners were taught 28 ASL verbs (14 iconic; 14 non-iconic) prior to performing these tasks. Only new learners benefited from sign iconicity, recognizing iconic translations faster and more accurately and exhibiting faster forward (English-ASL) and backward (ASL-English) translation times for iconic signs. In contrast, proficient ASL-English bilinguals exhibited slower recognition and translation times for iconic signs. We suggest iconicity aids memorization in the early stages of adult sign language learning, but for fluent L2 signers, iconicity interacts with other variables that slow translation (specifically, the iconic signs had more translation equivalents than the non-iconic signs). Iconicity may also have slowed translation performance by forcing conceptual mediation for iconic signs, which is slower than translating via direct lexical links.
PMCID: PMC3608132  PMID: 23543899
American Sign Language; iconicity; translation; bilingualism
25.  Medical reversal of chronic rhinosinusitis in a cystic fibrosis patient with ivacaftor 
Chronic sinusitis is universal in cystic fibrosis (CF) and our current treatments are ineffective in reversing sinus disease.
to determine if increasing CF transmembrane conductance regulator (CFTR) activity by ivacaftor could treat CF sinus disease and assess its effect on primary sinus epithelial cultures.
Case report of one patient with long-standing chronic sinus disease and a new diagnosis of CF with a mild mutation (P205S) and a severe mutation (G551D). We discuss clinical changes in symptoms, radiographic findings, nasal potential difference testing, and nasal pH values before and after treatment with ivacaftor. We then developed primary sinonasal epithelial cell cultures from a biopsy of the patient to determine changes in airway surface liquid (ASL) pH and ASL viscosity after ivacaftor treatment.
Ivacaftor treatment reversed CT findings of CF sinus disease, increased nasal voltage and pH and resolved sinus symptoms after ten months of therapy. Ivacaftor significantly increased ASL pH and decreased ASL viscosity in primary airway cultures.
This report documents the reversal of CF sinus disease. Based on our in vivo and in vitro results, we speculate that ivacaftor may reverse CF sinusitis by increasing ASL pH and decreasing ASL viscosity. These studies suggest that CFTR modulation may be effective in treating CF and perhaps non-CF sinusitis.
PMCID: PMC4310814  PMID: 25363320

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