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1.  Large-scale replication and heterogeneity in Parkinson disease genetic loci 
Sharma, Manu | Ioannidis, John P.A. | Aasly, Jan O. | Annesi, Grazia | Brice, Alexis | Van Broeckhoven, Christine | Bertram, Lars | Bozi, Maria | Crosiers, David | Clarke, Carl | Facheris, Maurizio | Farrer, Matthew | Garraux, Gaetan | Gispert, Suzana | Auburger, Georg | Vilariño-Güell, Carles | Hadjigeorgiou, Georgios M. | Hicks, Andrew A. | Hattori, Nobutaka | Jeon, Beom | Lesage, Suzanne | Lill, Christina M. | Lin, Juei-Jueng | Lynch, Timothy | Lichtner, Peter | Lang, Anthony E. | Mok, Vincent | Jasinska-Myga, Barbara | Mellick, George D. | Morrison, Karen E. | Opala, Grzegorz | Pramstaller, Peter P. | Pichler, Irene | Park, Sung Sup | Quattrone, Aldo | Rogaeva, Ekaterina | Ross, Owen A. | Stefanis, Leonidas | Stockton, Joanne D. | Satake, Wataru | Silburn, Peter A. | Theuns, Jessie | Tan, Eng-King | Toda, Tatsushi | Tomiyama, Hiroyuki | Uitti, Ryan J. | Wirdefeldt, Karin | Wszolek, Zbigniew | Xiromerisiou, Georgia | Yueh, Kuo-Chu | Zhao, Yi | Gasser, Thomas | Maraganore, Demetrius | Krüger, Rejko | Boyle, R.S | Sellbach, A | O'Sullivan, J.D. | Sutherland, G.T. | Siebert, G.A | Dissanayaka, N.N.W | Van Broeckhoven, Christine | Theuns, Jessie | Crosiers, David | Pickut, Barbara | Engelborghs, Sebastiaan | Meeus, Bram | De Deyn, Peter P. | Cras, Patrick | Rogaeva, Ekaterina | Lang, Anthony E | Agid, Y | Anheim, M | Bonnet, A-M | Borg, M | Brice, A | Broussolle, E | Corvol, JC | Damier, P | Destée, A | Dürr, A | Durif, F | Lesage, S | Lohmann, E | Pollak, P | Rascol, O | Tison, F | Tranchant, C | Viallet, F | Vidailhet, M | Tzourio, Christophe | Amouyel, Philippe | Loriot, Marie-Anne | Mutez, Eugénie | Duflot, Aurélie | Legendre, Jean-Philippe | Waucquier, Nawal | Gasser, Thomas | Riess, Olaf | Berg, Daniela | Schulte, Claudia | Klein, Christine | Djarmati, Ana | Hagenah, Johann | Lohmann, Katja | Auburger, Georg | Hilker, Rüdiger | van de Loo, Simone | Dardiotis, Efthimios | Tsimourtou, Vaia | Ralli, Styliani | Kountra, Persa | Patramani, Gianna | Vogiatzi, Cristina | Hattori, Nobutaka | Tomiyama, Hiroyuki | Funayama, Manabu | Yoshino, Hiroyo | Li, Yuanzhe | Imamichi, Yoko | Toda, Tatsushi | Satake, Wataru | Lynch, Tim | Gibson, J. Mark | Valente, Enza Maria | Ferraris, Alessandro | Dallapiccola, Bruno | Ialongo, Tamara | Brighina, Laura | Corradi, Barbara | Piolti, Roberto | Tarantino, Patrizia | Annesi, Ferdinanda | Jeon, Beom S. | Park, Sung-Sup | Aasly, J | Opala, Grzegorz | Jasinska-Myga, Barbara | Klodowska-Duda, Gabriela | Boczarska-Jedynak, Magdalena | Tan, Eng King | Belin, Andrea Carmine | Olson, Lars | Galter, Dagmar | Westerlund, Marie | Sydow, Olof | Nilsson, Christer | Puschmann, Andreas | Lin, JJ | Maraganore, Demetrius M. | Ahlskog, J, Eric | de Andrade, Mariza | Lesnick, Timothy G. | Rocca, Walter A. | Checkoway, Harvey | Ross, Owen A | Wszolek, Zbigniew K. | Uitti, Ryan J.
Neurology  2012;79(7):659-667.
Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.
Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.
In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78–0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14–1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.
Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity. Neurology® 2012;79:659–667
PMCID: PMC3414661  PMID: 22786590
2.  Diastereoselective Synthesis of γ- and δ-Lactams from Imines and Sulfone-Substituted Anhydrides 
The Journal of Organic Chemistry  2014;79(6):2601-2610.
Sulfone-substituted γ- and δ-lactams have been prepared in a single step with high diastereoselectivity. Sulfonylglutaric anhydrides produce intermediates that readily decarboxylate to provide δ-lactams with high diastereoselectivity. Substituents at the 3- or 4-position of the glutaric anhydride induce high levels of stereocontrol. Sulfonylsuccinic anhydrides produce intermediate carboxylic acids that can be trapped as methyl esters or allowed to decarboxylate under mild conditions. This method has been applied to a short synthesis of the pyrrolizidine alkaloid (±)-isoretronecanol.
PMCID: PMC3977582  PMID: 24552208
3.  Draft Genome Sequence of Rhodobacteraceae Strain PD-2, an Algicidal Bacterium with a Quorum-Sensing System, Isolated from the Marine Microalga Prorocentrum donghaiense 
Genome Announcements  2015;3(1):e01549-14.
Rhodobacteraceae strain PD-2 was isolated from the marine microalga Prorocentrum donghaiense. It has algicidal activity toward its host and could produce N-acylhomoserine lactone signals. Here, we present the draft genome of strain PD-2, which contains 5,227,214 bp with an average GC content of 66.19%. There were 4,864 encoding gene sequences and two clusters of luxI and luxR homologues identified.
PMCID: PMC4335330
4.  Ultrasensitive Online SERS Detection of Structural Isomers Separated by Capillary Zone Electrophoresis 
A mixture of structural isomers was separated and identified at nanomolar concentrations (~100,000 molecules) by incorporating capillary zone electrophoresis (CZE) with a sheath flow surface-enhanced Raman scattering (SERS) detector. Baseline resolution was obtained from three structural isomers of rhodamine using a planar silver SERS substrate, demonstrating the utility of this approach for trace chemical analysis.
PMCID: PMC3976900  PMID: 24395125
5.  Early Auditory Evoked Potential Is Modulated by Selective Attention and Related to Individual Differences in Visual Working Memory Capacity 
Journal of cognitive neuroscience  2014;26(12):2682-2690.
A growing body of research suggests that the predictive power of working memory (WM) capacity for measures of intellectual aptitude is due to the ability to control attention and select relevant information. Crucially, attentional mechanisms implicated in controlling access to WM are assumed to be domain-general, yet reports of enhanced attentional abilities in individuals with larger WM capacities are primarily within the visual domain. Here, we directly test the link between WM capacity and early attentional gating across sensory domains, hypothesizing that measures of visual WM capacity should predict an individual’s capacity to allocate auditory selective attention. To address this question, auditory ERPs were recorded in a linguistic dichotic listening task, and individual differences in ERP modulations by attention were correlated with estimates of WM capacity obtained in a separate visual change detection task. Auditory selective attention enhanced ERP amplitudes at an early latency (ca. 70–90 msec), with larger P1 components elicited by linguistic probes embedded in an attended narrative. Moreover, this effect was associated with greater individual estimates of visual WM capacity. These findings support the view that domain-general attentional control mechanisms underlie the wide variation of WM capacity across individuals.
PMCID: PMC4327887  PMID: 25000526
6.  Nitric Oxide (NO) Releasing Poly ADP-ribose Polymerase 1 (PARP-1) Inhibitors Targeted to Glutathione S-Transferase P1-Overexpressing Cancer Cells 
Journal of Medicinal Chemistry  2014;57(6):2292-2302.
We report the antitumor effects of nitric oxide (NO) releasing derivatives of the PARP-1 inhibitor olaparib (1). Compound 5b was prepared by coupling the carboxyl group of 3b and the free amino group of arylated diazeniumdiolated piperazine 4. Analogue 5a has the same structure except that the F is replaced by H. Compound 13 is the same as 5b except that a Me2N–N(O)=NO– group was added para and ortho to the nitro groups of the dinitrophenyl ring. The resulting prodrugs are activated by glutathione in a reaction accelerated by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancers. This metabolism generates NO plus a PARP-1 inhibitor simultaneously, consuming reducing equivalents, leading to DNA damage concomitant with inhibition of DNA repair, and in the case of 13 inducing cross-linking glutathionylation of proteins. Compounds 5b and 13 reduced the growth rates of A549 human lung adenocarcinoma xenografts with no evidence of systemic toxicity.
PMCID: PMC3983374  PMID: 24521039
7.  Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1 
Nature genetics  2014;46(8):886-890.
In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified three novel genetic loci associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene, P = 8.82 × 10−9), rs10474352 at 5q14.3 (near the ARRDC3 gene, P = 1.67 × 10−9), and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene, P = 4.25 × 10−8). These associations were replicated in European-ancestry populations including 16,003 cases and 41,335 controls (P = 0.030, 0.004, and 0.010, respectively). Data from the ENCODE project suggest that variants rs4951011 and rs10474352 may be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.
PMCID: PMC4127632  PMID: 25038754
8.  Enhanced GLT-1 mediated glutamate uptake and migration of primary astrocytes directed by fibronectin-coated electrospun poly-L-lactic acid fibers 
Biomaterials  2013;35(5):1439-1449.
Bioengineered fiber substrates are increasingly studied as a means to promote regeneration and remodeling in the injured central nervous system (CNS). Previous reports largely focused on the ability of oriented scaffolds to bridge injured regions and direct outgrowth of axonal projections. In the present work, we explored the effects of electrospun microfibers on the migration and physiological properties of brain astroglial cells. Primary rat astrocytes were cultured on either fibronectin-coated poly-l-lactic acid (PLLA) films, fibronectin-coated randomly oriented PLLA electrospun fibers, or fibronectin-coated aligned PLLA electrospun fibers. Aligned PLLA fibers strongly altered astrocytic morphology, orienting cell processes, actin microfilaments, and microtubules along the length of the fibers. On aligned fibers, astrocytes also significantly increased their migration rates in the direction of fiber orientation. We further investigated if fiber topography modifies astrocytic neuroprotective properties, namely glutamate and glutamine transport and metabolism. This was done by quantifying changes in mRNA expression (qRT-PCR) and protein levels (Western blotting) for a battery of relevant biomolecules. Interestingly, we found that cells grown on random and/or aligned fibers increased the expression levels of two glutamate transporters, GLAST and GLT-1, and an important metabolic enzyme, glutamine synthetase, as compared to the fibronectin-coated films. Functional assays revealed increases in glutamate transport rates due to GLT-1 mediated uptake, which was largely determined by the dihydrokainate-sensitive GLT-1. Overall, this study suggests that aligned PLLA fibers can promote directed astrocytic migration, and, of most importance, our in vitro results indicate for the first time that electrospun PLLA fibers can positively modify neuroprotective properties of glial cells by increasing rates of glutamate uptake.
PMCID: PMC4183153  PMID: 24246642
Poly-l-lactic acid; Aligned microfibers; Astrocytes; Migration; Glutamate transport; Glutamate metabolism
9.  Identification of a novel de novo p.Phe932Ile KCNT1 mutation in a patient with leukoencephalopathy and severe epilepsy 
Pediatric neurology  2013;50(1):112-114.
We present a male with early infantile epileptic encephalopathy (EIEE) and a leukoencephalopathy in whom whole exome family trio sequencing identified a heterozygous de novo mutation in KCNT1, a sodium gated potassium channel gene. Severely delayed myelination was anecdotally reported in previous cases with KCNT1 mutations. This case reinforces that KCNT1 sequencing should be included in an investigation of patients with severely delayed myelination and epilepsy.
PMCID: PMC4303471  PMID: 24120652
Leukoencephalopathy; Myoclonic; KCNT1; Delayed myelination
10.  Low Na, High K Diet and the Role of Aldosterone in BK-Mediated K Excretion 
PLoS ONE  2015;10(1):e0115515.
A low Na, high K diet (LNaHK) is associated with a low rate of cardiovascular (CV) disease in many societies. Part of the benefit of LNaHK relies on its diuretic effects; however, the role of aldosterone (aldo) in the diuresis is not understood. LNaHK mice exhibit an increase in renal K secretion that is dependent on the large, Ca-activated K channel, (BK-α with accessory BK-β4; BK-α/β4). We hypothesized that aldo causes an osmotic diuresis by increasing BK-α/β4-mediated K secretion in LNaHK mice. We found that the plasma aldo concentration (P[aldo]) was elevated by 10-fold in LNaHK mice compared with control diet (Con) mice. We subjected LNaHK mice to either sham surgery (sham), adrenalectomy (ADX) with low aldo replacement (ADX-LA), or ADX with high aldo replacement (ADX-HA). Compared to sham, the urinary flow, K excretion rate, transtubular K gradient (TTKG), and BK-α and BK-β4 expressions, were decreased in ADX-LA, but not different in ADX-HA. BK-β4 knockout (β4KO) and WT mice exhibited similar K clearance and TTKG in the ADX-LA groups; however, in sham and ADX-HA, the K clearance and TTKG of β4KO were less than WT. In response to amiloride treatment, the osmolar clearance was increased in WT Con, decreased in WT LNaHK, and unchanged in β4KO LNaHK. These data show that the high P[aldo] of LNaHK mice is necessary to generate a high rate of BK-α/β4-mediated K secretion, which creates an osmotic diuresis that may contribute to a reduction in CV disease.
PMCID: PMC4301648  PMID: 25607984
11.  Astrocytes Increase ATP Exocytosis Mediated Calcium Signaling in Response to Microgroove Structures 
Scientific Reports  2015;5:7847.
Following central nervous system (CNS) injury, activated astrocytes form glial scars, which inhibit axonal regeneration, leading to long-term functional deficits. Engineered nanoscale scaffolds guide cell growth and enhance regeneration within models of spinal cord injury. However, the effects of micro-/nanosize scaffolds on astrocyte function are not well characterized. In this study, a high throughput (HTP) microscale platform was developed to study astrocyte cell behavior on micropatterned surfaces containing 1 μm spacing grooves with a depth of 250 or 500 nm. Significant changes in cell and nuclear elongation and alignment on patterned surfaces were observed, compared to on flat surfaces. The cytoskeleton components (particularly actin filaments and focal adhesions) and nucleus-centrosome axis were aligned along the grooved direction as well. More interestingly, astrocytes on micropatterned surfaces showed enhanced mitochondrial activity with lysosomes localized at the lamellipodia of the cells, accompanied by enhanced adenosine triphosphate (ATP) release and calcium activities. These data indicate that the lysosome-mediated ATP exocytosis and calcium signaling may play an important role in astrocytic responses to substrate topology. These new findings have furthered our understanding of the biomechanical regulation of astrocyte cell–substrate interactions, and may benefit the optimization of scaffold design for CNS healing.
PMCID: PMC4297955  PMID: 25597401
12.  A Theoretical Framework for a Virtual Diabetes Self-Management Community Intervention 
Western journal of nursing research  2014;36(9):1222-1237.
Due to its high prevalence, chronic nature, potential complications, and self-management challenges for patients, diabetes presents significant health education and support issues. We developed and pilot-tested a virtual community for adults with type 2 diabetes to promote self-management education and provide social support. Although digital-based programs such as virtual environments can address significant barriers to reaching patients (i.e., child care, transportation, location), they must be strongly grounded in a theoretical basis to be well-developed and effective. In this article, we discuss how we synthesized behavioral and virtual environment theoretical frameworks to guide the development of SLIDES (Second Life Impacts Diabetes Education and Support).
PMCID: PMC4296559  PMID: 24451083
diabetes self-management education; type 2 diabetes; virtual environment; theoretical framework
13.  Alternative mating tactics in the yellow dung fly: resolving mechanisms of small-male advantage off pasture 
Recent work suggests that the yellow dung fly mating system may include alternative patroller–competitor mating tactics in which large males compete for gravid females on dung, whereas small, non-competitive males search for females at foraging sites. Small males obtain most matings off pasture, yet the behavioural mechanism(s) giving rise to this pattern are unknown. We investigated the male and female behaviours that determine mating success in this environment by conducting field mating experiments and found small males to benefit from several attributes specific to the off-pasture mating environment. First, small males from foraging sites exhibited higher mating propensity, indicating that large males away from dung may be depleted of energy and/or sperm. Second, small males were more discriminating, being significantly less likely to attempt with non-gravid females, which are absent on dung but common off pasture. Third, non-gravid females were generally more likely to actively struggle and reject mating attempts; however, such behaviours occurred disproportionately more often with large males. Female Scathophaga stercoraria thus appear to preferentially mate with small males when off pasture. These findings challenge assumptions about male–female interactions in systems with alternative mating tactics and reveal hidden processes that may influence selection patterns in the field.
PMCID: PMC3843829  PMID: 24225455
Scathophaga stercoraria; sexual selection; alternative mating tactics; female preference; male size
Annals of statistics  2014;42(2):413-468.
In the sparse linear regression setting, we consider testing the significance of the predictor variable that enters the current lasso model, in the sequence of models visited along the lasso solution path. We propose a simple test statistic based on lasso fitted values, called the covariance test statistic, and show that when the true model is linear, this statistic has an Exp(1) asymptotic distribution under the null hypothesis (the null being that all truly active variables are contained in the current lasso model). Our proof of this result for the special case of the first predictor to enter the model (i.e., testing for a single significant predictor variable against the global null) requires only weak assumptions on the predictor matrix X. On the other hand, our proof for a general step in the lasso path places further technical assumptions on X and the generative model, but still allows for the important high-dimensional case p > n, and does not necessarily require that the current lasso model achieves perfect recovery of the truly active variables.
Of course, for testing the significance of an additional variable between two nested linear models, one typically uses the chi-squared test, comparing the drop in residual sum of squares (RSS) to a χ12 distribution. But when this additional variable is not fixed, and has been chosen adaptively or greedily, this test is no longer appropriate: adaptivity makes the drop in RSS stochastically much larger than χ12 under the null hypothesis. Our analysis explicitly accounts for adaptivity, as it must, since the lasso builds an adaptive sequence of linear models as the tuning parameter λ decreases. In this analysis, shrinkage plays a key role: though additional variables are chosen adaptively, the coefficients of lasso active variables are shrunken due to the l1 penalty. Therefore, the test statistic (which is based on lasso fitted values) is in a sense balanced by these two opposing properties—adaptivity and shrinkage—and its null distribution is tractable and asymptotically Exp(1).
PMCID: PMC4285373  PMID: 25574062
Lasso; least angle regression; p-value; significance test
15.  An Injectable, Calcium Responsive Composite Hydrogel for the Treatment of Acute Spinal Cord Injury 
ACS Applied Materials & Interfaces  2014;6(3):1424-1438.
Immediately following spinal cord injury, further injury can occur through several secondary injury cascades. As a consequence of cell lysis, an increase in extracellular Ca2+ results in additional neuronal loss by inducing apoptosis. Thus, hydrogels that reduce extracellular Ca2+ concentration may reduce secondary injury severity. The goal of this study was to develop composite hydrogels consisting of alginate, chitosan, and genipin that interact with extracellular Ca2+ to enable in situ gelation while maintaining an elastic modulus similar to native spinal cord (∼1000 Pa). It was hypothesized that incorporation of genipin and chitosan would regulate hydrogel electrostatic characteristics and influence hydrogel porosity, degradation, and astrocyte behavior. Hydrogel composition was varied to create hydrogels with statistically similar mechanical properties (∼1000 Pa) that demonstrated tunable charge characteristics (6-fold range in free amine concentration) and degradation rate (complete degradation between 7 and 28 days; some blends persist after 28 days). Hydrogels demonstrate high sensitivity to Ca2+ concentration, as a 1 mM change during fabrication induced a significant change in elastic modulus. Additionally, hydrogels incubated in a Ca2+-containing solution exhibited an increased linear viscoelastic limit (LVE) and an increased elastic modulus above the LVE limit in a time dependent manner. An extension of the LVE limit implies a change in hydrogel cross-linking structure. Attachment assays demonstrated that addition of chitosan/genipin to alginate hydrogels induced up to a 4-fold increase in the number of attached astrocytes and facilitated astrocyte clustering on the hydrogel surface in a composition dependent manner. Furthermore, Western blots demonstrated tunable glial fibrillary acid protein (GFAP) expression in astrocytes cultured on hydrogel blends, with some hydrogel compositions demonstrating no significant increase in GFAP expression compared to astrocytes cultured on glass. Thus, alginate/chitosan/genipin hydrogel composites show promise as scaffolds that regulate astrocyte behavior and for the prevention of Ca2+-related secondary neuron damage during acute SCI.
PMCID: PMC3982972  PMID: 24397537
alginate; chitosan; hydrogel; astrocytes; spinal cord injury; glial fibrillary acidic protein
16.  Preservation of Capillary-beds in Rat Lung Tissue Using Optimized Chemical Decellularization 
Promoting regeneration using scaffolds created by decellularizing native tissue is becoming a popular technique applied to a variety of tissues. We demonstrate a method to decellularize highly vascular tissue keeping the vascular structure intact down to the capillary scale. Using vascular corrosion casting (VCC), we created a method for quantitatively assessing the functionality of vascular extracellular matrix (ECM) following decellularization. Murine lung tissue was decellularized using a number of techniques, then characterized using standard histological methods, as well as our quantitative VCC (qVCC) technique. Using an optimized acellular method, we successfully decellularized lung tissue while leaving behind a patent vascular network based on qualitative and quantitative histological methods.
PMCID: PMC4281942  PMID: 25558373
17.  The protective effect of LRRK2 p.R1398H on risk of Parkinson’s disease is independent of MAPT and SNCA variants 
Neurobiology of aging  2013;35(1):10.1016/j.neurobiolaging.2013.07.013.
The best validated susceptibility variants for Parkinson’s disease (PD) are located in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined four SNCA variants (rs181489, rs356219, rs11931074, rs2583988), the MAPT H1-haplotype defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (N=10,322) and Asian (N=2,289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all P≥0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with PD is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.
PMCID: PMC3829604  PMID: 23962496
Parkinson disease; LRRK2; SNCA; MAPT; interaction; genetics
18.  BRAF-V600E mutation in pediatric and adult glioblastoma 
Neuro-Oncology  2013;16(2):318-319.
PMCID: PMC3895374  PMID: 24311634
brain tumor; children; glioma; microarray
19.  “NEDD9 Depletion Leads to MMP14 Inactivation by TIMP2 and Prevents Invasion and Metastasis.” 
The scaffolding protein NEDD9 is an established pro-metastatic marker in several cancers. Nevertheless, the molecular mechanisms of NEDD9 driven metastasis in cancers remain ill defined. Here, using a comprehensive breast cancer (BCa) tissue microarray, it was show that increased levels of NEDD9 protein significantly correlated with the transition from carcinoma in situ to invasive carcinoma. Similarly, it was shown that NEDD9 overexpression is a hallmark of highly invasive BCa cells. Moreover, NEDD9 expression is crucial for the protease-dependent mesenchymal invasion of cancer cells at the primary site but not at the metastatic site. Depletion of NEDD9 is sufficient to suppress invasion of tumor cells in vitro and in vivo, leading to decreased circulating tumor cells (CTCs) and lung metastases in xenograft models. Mechanistically, NEDD9 localized to invasive pseudopods and was required for local matrix degradation. Depletion of NEDD9 impaired invasion of cancer cells through inactivation of membrane-bound matrix metalloproteinase MMP14 by excess TIMP2 on the cell surface. Inactivation of MMP14 is accompanied by reduced collagenolytic activity of soluble metalloproteinases MMP2 and MMP9. Re-expression of NEDD9 is sufficient to restore the activity of MMP14 and the invasive properties of BCa cells in vitro and in vivo. Collectively, these findings uncover critical steps in NEDD9-dependent invasion of BCa cells.
This study provides a mechanistic basis for potential therapeutic interventions to prevent metastasis.
PMCID: PMC3946989  PMID: 24202705
NEDD9; invasion, metastasis; breast cancer; MMP14
20.  A composite outcome for neonatal cardiac surgery research 
The objective of this study was to determine whether a composite outcome, derived of objective signs of inadequate cardiac output, would be associated with other important measures of outcomes and therefore be an appropriate end point for clinical trials in neonatal cardiac surgery.
Neonates (n = 76) undergoing cardiac operations requiring cardiopulmonary bypass were prospectively enrolled. Patients were defined to have met the composite outcome if they had any of the following events before hospital discharge: death, the use of mechanical circulatory support, cardiac arrest requiring chest compressions, hepatic injury (2 times the upper limit of normal for aspartate aminotransferase or alanine aminotransferase), renal injury (creatinine >1.5 mg/dL), or lactic acidosis (an increasing lactate >5 mmol/L in the postoperative period). Associations between the composite outcome and the duration of mechanical ventilation, intensive care unit stay, hospital stay, and total hospital charges were determined.
The median age at the time of surgery was 7 days, and the median weight was 3.2 kg. The composite outcome was met in 39% of patients (30/76). Patients who met the composite outcome compared with those who did not had a longer duration of mechanical ventilation (4.9 vs 2.9 days, P<.01), intensive care unit stay (8.8 vs 5.7 days, P<.01), hospital stay (23 vs 12 days, P<.01), and increased hospital charges ($258,000 vs $170,000, P<.01). In linear regression analysis, controlling for surgical complexity, these differences remained significant (R2 = 0.29–0.42, P<.01).
The composite outcome is highly associated with important early operative outcomes and may serve as a useful end point for future clinical research in neonates undergoing cardiac operations.
PMCID: PMC4004075  PMID: 23587468
21.  Mechanism of Algal Aggregation by Bacillus sp. Strain RP1137 
Applied and Environmental Microbiology  2014;80(13):4042-4050.
Alga-derived biofuels are one of the best alternatives for economically replacing liquid fossil fuels with a fungible renewable energy source. Production of fuel from algae is technically feasible but not yet economically viable. Harvest of dilute algal biomass from the surrounding water remains one of the largest barriers to economic production of algal biofuel. We identified Bacillus sp. strain RP1137 in a previous study and showed that this strain can rapidly aggregate several biofuel-producing algae in a pH- and divalent-cation-dependent manner. In this study, we further characterized the mechanism of algal aggregation by RP1137. We show that aggregation of both algae and bacteria is optimal in the exponential phase of growth and that the density of ionizable residues on the RP1137 cell surface changes with growth stage. Aggregation likely occurs via charge neutralization with calcium ions at the cell surface of both algae and bacteria. We show that charge neutralization occurs at least in part through binding of calcium to negatively charged teichoic acid residues. The addition of calcium also renders both algae and bacteria more able to bind to hydrophobic beads, suggesting that aggregation may occur through hydrophobic interactions. Knowledge of the aggregation mechanism may enable engineering of RP1137 to obtain more efficient algal harvesting.
PMCID: PMC4054200  PMID: 24771029
22.  Coronary endothelial function in patients with obstructive sleep apnea 
Coronary artery disease  2014;25(1):16-22.
Obstructive sleep apnea (OSA) has been associated with increased risk for cardiovascular events, possibly mediated by endothelial dysfunction. The current study evaluates the association between invasive coronary endothelial dysfunction and OSA in patients with nonobstructive coronary atherosclerosis.
All patients who had undergone both polysomnography and an invasive coronary vasomotor study at the Mayo Clinic, Rochester, Minnesota, from January 1997 to August 2011 were identified (n= 143). OSA was defined as an apnea–hypopnea index of 5 or higher. Three endpoints of coronary endothelial function – percentage change in coronary artery diameter at the mid and distal left anterior descending artery to intracoronary acetylcholine and percentage change in coronary blood flow to intracoronary acetylcholine – were assessed. Differences between patients with OSA (n= 102) and those without OSA (n= 41) were evaluated using multivariate analysis of variance. Follow-up mortality data were collected and Kaplan–Meier curves were plotted to evaluate differences in mortality between patients with and without OSA.
Patients with OSA were more likely to have hypertension compared with patients without OSA. OSA was not significantly associated with coronary endothelial dysfunction on univariate analysis (P = 0.23) and after adjustment for hypertension (P = 0.19). Similarly, there was no significant difference in coronary endothelial function in patients who had oxygen desaturation of less than 90% during polysomnography (P = 0.42). There was a trend toward higher mortality in patients with OSA compared with those without OSA, but this did not reach statistical significance (5 vs. 0% at 10 years, P =0.25).
The current study suggests that OSA is not an independent risk factor for coronary endothelial dysfunction in patients with early coronary atherosclerosis. Adverse coronary outcomes in patients with OSA may be independent of coronary endothelial dysfunction. Coron
PMCID: PMC4073497  PMID: 24220674
acetylcholine; coronary artery diameter; coronary blood flow; coronary risk factor; endothelial dysfunction; obstructive sleep apnea
23.  Relation between BK-α/β4-mediated potassium secretion and ENaC-mediated sodium reabsorption 
Kidney international  2014;86(1):139-145.
The large conductance, calcium-activated BK-α/β4 potassium channel, localized to the intercalated cells of the distal nephron, mediates potassium secretion during high potassium, alkaline diets. Here we determine whether BK-α/β4-mediated potassium transport is dependent on epithelial sodium channel (ENaC)-mediated sodium reabsorption. We maximized sodium-potassium exchange in the distal nephron by feeding mice a low sodium, high potassium diet. Wild type and BK-β4 knockout mice were maintained on low sodium, high potassium, alkaline diet or a low sodium, high potassium, acidic diet for 7–10 days. Wild type mice maintained potassium homeostasis on the alkaline but not acid diet. BK-β4 knockout mice could not maintain potassium homeostasis on either diet. During the last 12 hours of diet, wild type mice on either a regular, alkaline or an acid diet, or knockout mice on an alkaline diet were administered amiloride (an ENaC inhibitor). Amiloride enhanced sodium excretion in all wild type and knockout groups to similar values; however, amiloride diminished potassium excretion by 59% in wild type but only by 33% in knockout mice on an alkaline diet. Similarly, amiloride decreased the transtubular potassium gradient by 68% in wild type but only by 42% in knockout mice on an alkaline diet. Amiloride treatment equally enhanced sodium excretion and diminished potassium secretion in knockout mice on an alkaline diet and wild type mice on an acid diet. Thus, the enhanced effect of amiloride on potassium secretion in wild type compared to knockout mice on the alkaline diet, clarify a BK- α/β4-mediated potassium secretory pathway in intercalated cells driven by ENaC-mediated sodium reabsorption linked to bicarbonate secretion.
PMCID: PMC4077913  PMID: 24573316
BK-α/β4; ENaC; K secretion; Na reabsorption; intercalated cell; TTKG; math modeling
24.  Update on novel familial forms of Parkinson’s disease and multiple system atrophy 
Parkinsonism & related disorders  2014;20(0 1):S29-S34.
Parkinson’s disease (PD) and multiple system atrophy (MSA) are progressive neurodegenerative disorders classified as synucleinopathies, which are defined by the presence of α-synuclein protein pathology. Genetic studies have identified a total of 18 PARK loci that are associated with PD. The SNCA gene encodes the α-synuclein protein. The first pathogenic α-synuclein p.A53T substitution was discovered in 1997; this was followed by the identification of p.A30P and p.E46K pathogenic substitutions in 1998 and 2004, respectively. In the last year, two possible α-synuclein pathogenic substitutions, p.A18T and p.A29S, and two probable pathogenic substitutions, p.H50Q and p.G51D have been nominated. Next-generation sequencing approaches in familial PD have identified mutations in the VPS35 gene. A VPS35 p.D620N substitution remains the only confirmed pathogenic substitution. A second synucleinopathy, MSA, originally was considered a sporadic condition with little or no familial aggregation. However, recessive COQ2 mutations recently were nominated to be the genetic cause in a subset of familial and sporadic MSA cases. Further studies on the clinicogenetics and pathology of parkinsonian disorders will facilitate clarification of the molecular characteristics and pathomechanisms underlying these disorders.
PMCID: PMC4215194  PMID: 24262183
SNCA; VPS35; PD; MSA; Genetics; Familial
25.  A single genus in the gut microbiome reflects host preference and specificity 
The ISME Journal  2014;9(1):90-100.
Delineating differences in gut microbiomes of human and animal hosts contributes towards understanding human health and enables new strategies for detecting reservoirs of waterborne human pathogens. We focused upon Blautia, a single microbial genus that is important for nutrient assimilation as preliminary work suggested host-related patterns within members of this genus. In our dataset of 57 M sequence reads of the V6 region of the 16S ribosomal RNA gene in samples collected from seven host species, we identified 200 high-resolution taxonomic units within Blautia using oligotyping. Our analysis revealed 13 host-specific oligotypes that occurred exclusively in fecal samples of humans (three oligotypes), swine (six oligotypes), cows (one oligotype), deer (one oligotype), or chickens (two oligotypes). We identified an additional 171 oligotypes that exhibited differential abundance patterns among all the host species. Blautia oligotypes in the human population obtained from sewage and fecal samples displayed remarkable continuity. Oligotypes from only 10 Brazilian human fecal samples collected from individuals in a rural village encompassed 97% of all Blautia oligotypes found in a Brazilian sewage sample from a city of three million people. Further, 75% of the oligotypes in Brazilian human fecal samples matched those in US sewage samples, implying that a universal set of Blautia strains may be shared among culturally and geographically distinct human populations. Such strains can serve as universal markers to assess human fecal contamination in environmental samples. Our results indicate that host-specificity and host-preference patterns of organisms within this genus are driven by host physiology more than dietary habits.
PMCID: PMC4274434  PMID: 24936765

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