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1.  Identification of Genetic Determinants of the Sexual Dimorphism in CNS Autoimmunity 
PLoS ONE  2015;10(2):e0117993.
Multiple sclerosis (MS) is a debilitating chronic inflammatory disease of the nervous system that affects approximately 2.3 million individuals worldwide, with higher prevalence in females, and a strong genetic component. While over 200 MS susceptibility loci have been identified in GWAS, the underlying mechanisms whereby they contribute to disease susceptibility remains ill-defined. Forward genetics approaches using conventional laboratory mouse strains are useful in identifying and functionally dissecting genes controlling disease-relevant phenotypes, but are hindered by the limited genetic diversity represented in such strains. To address this, we have combined the powerful chromosome substitution (consomic) strain approach with the genetic diversity of a wild-derived inbred mouse strain. Using experimental allergic encephalomyelitis (EAE), a mouse model of MS, we evaluated genetic control of disease course among a panel of 26 consomic strains of mice inheriting chromosomes from the wild-derived PWD strain on the C57BL/6J background, which models the genetic diversity seen in human populations. Nineteen linkages on 18 chromosomes were found to harbor loci controlling EAE. Of these 19 linkages, six were male-specific, four were female-specific, and nine were non-sex-specific, consistent with a differential genetic control of disease course between males and females. An MS-GWAS candidate-driven bioinformatic analysis using orthologous genes linked to EAE course identified sex-specific and non-sex-specific gene networks underlying disease pathogenesis. An analysis of sex hormone regulation of genes within these networks identified several key molecules, prominently including the MAP kinase family, known hormone-dependent regulators of sex differences in EAE course. Importantly, our results provide the framework by which consomic mouse strains with overall genome-wide genetic diversity, approximating that seen in humans, can be used as a rapid and powerful tool for modeling the genetic architecture of MS. Moreover, our data represent the first step towards mechanistic dissection of genetic control of sexual dimorphism in CNS autoimmunity.
PMCID: PMC4324900  PMID: 25671658
2.  Rac1 modification by an electrophilic 15-deoxy Δ12,14-prostaglandin J2 analog 
Redox Biology  2015;4:346-354.
Vascular endothelial cells (ECs) are important for maintaining vascular homeostasis. Dysfunction of ECs contributes to cardiovascular diseases, including atherosclerosis, and can impair the healing process during vascular injury. An important mediator of EC response to stress is the GTPase Rac1. Rac1 responds to extracellular signals and is involved in cytoskeletal rearrangement, reactive oxygen species generation and cell cycle progression. Rac1 interacts with effector proteins to elicit EC spreading and formation of cell-to-cell junctions. Rac1 activity has recently been shown to be modulated by glutathiolation or S-nitrosation via an active site cysteine residue. However, it is not known whether other redox signaling compounds can modulate Rac1 activity. An important redox signaling mediator is the electrophilic lipid, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). This compound is a downstream product of cyclooxygenase and forms covalent adducts with specific cysteine residues, and induces cellular signaling in a pleiotropic manner. In this study, we demonstrate that a biotin-tagged analog of 15d-PGJ2 (bt-15d-PGJ2) forms an adduct with Rac1 in vitro at the C157 residue, and an additional adduct was detected on the tryptic peptide associated with C178. Rac1 modification in addition to modulation of Rac1 activity by bt-15d-PGJ2 was observed in cultured ECs. In addition, decreased EC migration and cell spreading were observed in response to the electrophile. These results demonstrate for the first time that Rac1 is a target for 15d-PGJ2 in ECs, and suggest that Rac1 modification by electrophiles such as 15d-PGJ2 may alter redox signaling and EC function.
Graphical abstract
• Recombinant Rac1 is modified by bt-15d-PGJ2 at C157 in vitro.• Rac1 is modified by bt-15d-PGJ2 in bovine aortic endothelial cells.• Rac1 activity is transiently stimulated by bt-15d-PGJ2.• 15d-PGJ2 inhibits endothelial cell migration and spreading.
PMCID: PMC4326178  PMID: 25677088
Cyclopentenone; Electrophile responsive proteome; Oxidative post-translational modification; Redox signaling; Rho GTPase; Thiol; 15d-PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; BAEC, bovine aortic endothelial cells; DMEM, Dulbecco's Modified Eagle's Medium; EC, endothelial cells; EDTA, ethylenediamine tetraacetic acid; FBS, fetal bovine serum; GST-A, glutathione agarose; GST, glutathione-S-transferase; PBS, phosphate-buffered saline; PIC, protease inhibitor cocktail; PBD, protein binding domain; SDS, sodium dodecyl sulfate; Ras-Related C3 Botulinum Toxin Substrate1 Aliases, cell migration-inducing gene 5 protein, TC-25, Ras-like protein TC25, Ras-related C3 botulinum toxin substrate 1, p21-Rac1, TC25
3.  High Prevalence and Diversity of Kidney Dysfunction in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease: The BARI 2D Baseline Data 
We describe baseline renal function and albumin excretion rate in patients enrolled in BARI 2D, a randomized clinical trial comparing revascularization and medical therapy with medical therapy alone and deferred or no revascularization, and the impact of glycemic control with either insulin providing or insulin sensitizing drugs, on 5 year mortality.
Study participants had T2DM, documented CAD, and creatinine < 2 mg/dl. Albuminuria status (albumin/creatinine ratio [ACR]) and estimated glomerular filtration rate (eGFR), utilizing the abbreviated MDRD equation, were determined at baseline. Univariate and multivariate relationships between baseline clinical characteristics and the presence of albuminuria and reduced eGFR rate were estimated.
2146 subjects were included in the analysis. 43% of the cohort had evidence of kidney dysfunction at baseline: 23% had an eGFR ≥ 60 ml/min/1.73 m2 with either micro (>30 ACR; 17%) or macro (> 300 ACR; 6%) albuminuria. 21 % had a reduced eGFR < 60 ml/min/1.73 m2; 52 % with reduced eGFR had no albuminuria; 28 % had microalbuminuria and 20 % had macroalbuminuria. Race, smoking status, duration of diabetes, hypertension, HbA1c, triglycerides, vascular disease, abnormal ejection fraction, and reduced eGFR were associated with greater albuminuria. Age, sex, duration of diabetes, ACR, HbA1c, HDL, and number of hypertensive medications were associated with reduced eGFR.
Kidney dysfunction is common in older patients with T2DM and CAD; Albuminuria was present in 33%. Reduced eGFR was present in 21%, and half the patients with reduced eGFR had no evidence of albuminuria.
PMCID: PMC4312489  PMID: 20375690
4.  The Development of the DSM-5 Cultural Formulation Interview-Fidelity Instrument (CFI-FI): A Pilot Study 
This paper reports on the development of the Cultural Formulation Interview-Fidelity Instrument (CFI-FI) which assesses clinician fidelity to the DSM-5 Cultural Formulation Interview (CFI). The CFI consists of a manualized set of standard questions that can precede every psychiatric evaluation. It is based on the DSM-IV Outline for Cultural Formulation, the cross-cultural assessment with the most evidence in psychiatric training. Using the New York sample of the DSM-5 CFI field trial, two independent raters created and finalized items for the CFI-FI based on six audio-taped and transcribed interviews. The raters then used the final CFI-FI to rate the remaining 23 interviews. Inter-rater reliability ranged from .73 to 1 for adherence items and .52 to 1 for competence items. The development of the CFI-FI can help researchers and administrators determine whether the CFI has been implemented with fidelity, permitting future intervention research.
PMCID: PMC4306341  PMID: 25130248
Cultural psychiatry; cultural formulation; fidelity; cultural competence; health disparities
5.  Large-amplitude internal waves benefit corals during thermal stress 
Tropical scleractinian corals are particularly vulnerable to global warming as elevated sea surface temperatures (SSTs) disrupt the delicate balance between the coral host and their algal endosymbionts, leading to symbiont expulsion, mass bleaching and mortality. While satellite sensing of SST has proved a reliable predictor of coral bleaching at the regional scale, there are large deviations in bleaching severity and mortality on the local scale that are poorly understood. Here, we show that internal waves play a major role in explaining local coral bleaching and mortality patterns in the Andaman Sea. Despite a severe region-wide SST anomaly in May 2010, frequent upslope intrusions of cold sub-pycnocline waters due to breaking large-amplitude internal waves (LAIW) mitigated coral bleaching and mortality in shallow waters. In LAIW-sheltered waters, by contrast, bleaching-susceptible species suffered severe bleaching and total mortality. These findings suggest that LAIW benefit coral reefs during thermal stress and provide local refugia for bleaching-susceptible corals. LAIW are ubiquitous in tropical stratified waters and their swash zones may thus be important conservation areas for the maintenance of coral diversity in a warming climate. Taking LAIW into account can significantly improve coral bleaching predictions and provide a valuable tool for coral reef conservation and management.
PMCID: PMC4286055  PMID: 25473004
coral bleaching; large-amplitude internal waves; solitons; cooling; global warming
6.  Finding Our Way through Phenotypes 
Deans, Andrew R. | Lewis, Suzanna E. | Huala, Eva | Anzaldo, Salvatore S. | Ashburner, Michael | Balhoff, James P. | Blackburn, David C. | Blake, Judith A. | Burleigh, J. Gordon | Chanet, Bruno | Cooper, Laurel D. | Courtot, Mélanie | Csösz, Sándor | Cui, Hong | Dahdul, Wasila | Das, Sandip | Dececchi, T. Alexander | Dettai, Agnes | Diogo, Rui | Druzinsky, Robert E. | Dumontier, Michel | Franz, Nico M. | Friedrich, Frank | Gkoutos, George V. | Haendel, Melissa | Harmon, Luke J. | Hayamizu, Terry F. | He, Yongqun | Hines, Heather M. | Ibrahim, Nizar | Jackson, Laura M. | Jaiswal, Pankaj | James-Zorn, Christina | Köhler, Sebastian | Lecointre, Guillaume | Lapp, Hilmar | Lawrence, Carolyn J. | Le Novère, Nicolas | Lundberg, John G. | Macklin, James | Mast, Austin R. | Midford, Peter E. | Mikó, István | Mungall, Christopher J. | Oellrich, Anika | Osumi-Sutherland, David | Parkinson, Helen | Ramírez, Martín J. | Richter, Stefan | Robinson, Peter N. | Ruttenberg, Alan | Schulz, Katja S. | Segerdell, Erik | Seltmann, Katja C. | Sharkey, Michael J. | Smith, Aaron D. | Smith, Barry | Specht, Chelsea D. | Squires, R. Burke | Thacker, Robert W. | Thessen, Anne | Fernandez-Triana, Jose | Vihinen, Mauno | Vize, Peter D. | Vogt, Lars | Wall, Christine E. | Walls, Ramona L. | Westerfeld, Monte | Wharton, Robert A. | Wirkner, Christian S. | Woolley, James B. | Yoder, Matthew J. | Zorn, Aaron M. | Mabee, Paula
PLoS Biology  2015;13(1):e1002033.
Imagine if we could compute across phenotype data as easily as genomic data; this article calls for efforts to realize this vision and discusses the potential benefits.
Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility.
PMCID: PMC4285398  PMID: 25562316
7.  Cyclic Tensile Strain Enhances Osteogenesis and Angiogenesis in Mesenchymal Stem Cells from Osteoporotic Donors 
Tissue Engineering. Part A  2013;20(1-2):67-78.
We have shown that the uniaxial cyclic tensile strain of magnitude 10% promotes and enhances osteogenesis of human mesenchymal stem cells (hMSC) and human adipose-derived stem cells (hASC) from normal, nonosteoporotic donors. In the present study, MSC from osteoporotic donors were analyzed for changes in mRNA expression in response to 10% uniaxial tensile strain to identify potential mechanisms underlying the use of this mechanical loading paradigm for prevention and treatment of osteoporosis. Human MSC isolated from three female, postmenopausal osteoporotic donors were analyzed for their responses to mechanical loading using microarray analysis of over 47,000 gene probes. Human MSC were seeded in three-dimensional collagen type I constructs to mimic the organic extracellular matrix of bone and 10% uniaxial cyclic tensile strain was applied to promote osteogenesis. Seventy-nine genes were shown to be regulated within hMSC from osteoporotic donors in response to 10% cyclic tensile strain. Upregulation of six genes were further confirmed with real-time RT-PCR: jun D proto-oncogene (JUND) and plasminogen activator, urokinase receptor (PLAUR), two genes identified as potential key molecules from network analysis; phosphoinositide-3-kinase, catalytic, delta polypeptide (PIK3CD) and wingless-type MMTV integration site family, member 5B (WNT5B), two genes with known importance in bone biology; and, PDZ and LIM domain 4 (PDLIM4) and vascular endothelial growth factor A (VEGFA), two genes that we have previously shown are significantly regulated in hASC in response to this mechanical stimulus. Function analysis indicated that 10% cyclic tensile strain induced expression of genes associated with cell movement, cell proliferation, and tissue development, including development in musculoskeletal and cardiovascular systems. Our results demonstrate that hMSC from aged, osteoporotic donors are capable of enhanced osteogenic differentiation in response to 10% cyclic tensile strain with significant increases in the expression of genes associated with enhanced cell proliferation, musculoskeletal development, and angiogenesis. Surprisingly, cyclic tensile strain of magnitude 10% not only enhanced osteogenesis in hMSC from osteoporotic donors, but also enhanced expression of angiogenic factors. Better understanding and methodologies to promote osteogenesis in hMSC from elderly, osteoporotic donors may greatly facilitate achieving long-term success in bone regeneration and functional bone tissue engineering for this ever-growing patient population.
PMCID: PMC3875187  PMID: 23927731
8.  Molecular recognition in myxobacterial outer membrane exchange: Functional, social and evolutionary implications 
Molecular microbiology  2013;91(2):209-220.
Through cooperative interactions, bacteria can build multicellular communities. To ensure that productive interactions occur, bacteria must recognize their neighbors and respond accordingly. Molecular recognition between cells is thus a fundamental behavior, and in bacteria important discoveries have been made. This MicroReview focuses on a recently described recognition system in myxobacteria that is governed by a polymorphic cell surface receptor called TraA. TraA regulates outer membrane exchange (OME), whereby myxobacterial cells transiently fuse their OMs to efficiently transfer proteins and lipids between cells. Unlike other transport systems, OME is rather indiscriminate in what OM goods are transferred. In contrast, the recognition of partnering cells is discriminatory and only occurs between cells that bear identical or closely related TraA proteins. Therefore TraA functions in kin recognition and, in turn, OME helps regulate social interactions between myxobacteria. Here, I discuss and speculate on the social and evolutionary implications of OME and suggest it helps to guide their transition from free-living cells into coherent and functional populations.
PMCID: PMC3900325  PMID: 24261719
Recognition; membrane fusion; Myxococcus xanthus
9.  The Prevalence of Undiagnosed HIV Serodiscordance among Male Couples Presenting for HIV Testing 
Archives of sexual behavior  2014;43(1):173-180.
In the United States, a substantial proportion of HIV transmissions among men who have sex with men (MSM) arise from main sex partners. Couples voluntary HIV testing and counseling (CHTC) is used in many parts of the world with male-female couples, but CHTC has historically not been available in the U.S. and few data exist about the extent of HIV serodiscordance among U.S. male couples. We tested partners in 95 Atlanta male couples (190 men) for HIV. Eligible men were in a relationship for ≥ 3 months and were not known to be HIV-positive. We calculated the prevalence of couples that were seroconcordant HIV-negative, seroconcordant HIV-positive, or HIV serodiscordant. We evaluated differences in the prevalence of HIV serodiscordance by several dyadic characteristics (e.g., duration of relationship, sexual agreements, and history of anal intercourse in the relationship). Overall, among 190 men tested for HIV, 11% (n = 20) were newly identified as HIV-positive. Among the 95 couples, 81% (n = 77) were concordant HIV-negative, 17% (n = 16) were HIV serodiscordant, and 2% (n=2) were concordant HIV-positive. Serodiscordance was not significantly associated with any evaluated dyadic characteristic. The prevalence of undiagnosed HIV serodiscordance among male couples in Atlanta is high. Offering testing to male couples may attract men with a high HIV seropositivity rate to utilize testing services. Based on the global evidence base for CHTC with heterosexual couples and the current evidence of substantial undiagnosed HIV serodiscordance among U.S. MSM, we recommend scale-up of CHTC services for MSM, with ongoing evaluation of acceptability and couples’ serostatus outcomes.
PMCID: PMC3945405  PMID: 24233391
HIV; men who have sex with men; HIV testing; male couples; sexual orientation
10.  Validation of a Patient-Centered, Culturally Sensitive, Clinic Environment Inventory Using a National Sample of Adult Patients 
The purpose of this study was to determine the factor structure, internal consistency reliability, and validity of the Tucker Culturally Sensitive Health Care Clinic Environment Inventory–Patient Form (T-CSHCCEI-PF), a novel instrument designed to assess an aspect of health care often ignored in health care quality research: the cultural sensitivity of health care center policies and environment as perceived by adult, racially/ethnically diverse patients. Using ratings on this inventory by a culturally diverse national sample of adult patients (N = 1,639) from 67 health care sites across the United States, a confirmatory factor analysis of the T-CSHCCEI-PF was conducted, and its reliability and validity were determined. The T-CSHCCEI-PF was shown to be a reliable and valid inventory for culturally diverse patients to provide feedback to the administrators at their health care centers regarding the degree to which these centers have characteristics that are reflective of patient-centered culturally sensitive health care.
PMCID: PMC4117241  PMID: 24129544
patient-centered care; clinic environment cultural sensitivity; patient satisfaction; patient evaluation of clinic environment; Tucker Culturally Sensitive Health Care Clinic Environment Inventory-Patient Form (T-CSHCCEI-PF)
11.  Epidemiology and Risk Factors for Idiopathic Intracranial Hypertension 
International ophthalmology clinics  2014;54(1):10.1097/IIO.0b013e3182aabf11.
PMCID: PMC3864361  PMID: 24296367
idiopathic intracranial hypertension; pseudotumor cerebri; papilledema; epidemiology; risk factors
12.  Fish Sound Production in the Presence of Harmful Algal Blooms in the Eastern Gulf of Mexico 
PLoS ONE  2014;9(12):e114893.
This paper presents the first known research to examine sound production by fishes during harmful algal blooms (HABs). Most fish sound production is species-specific and repetitive, enabling passive acoustic monitoring to identify the distribution and behavior of soniferous species. Autonomous gliders that collect passive acoustic data and environmental data concurrently can be used to establish the oceanographic conditions surrounding sound-producing organisms. Three passive acoustic glider missions were conducted off west-central Florida in October 2011, and September and October 2012. The deployment period for two missions was dictated by the presence of red tide events with the glider path specifically set to encounter toxic Karenia brevis blooms (a.k.a red tides). Oceanographic conditions measured by the glider were significantly correlated to the variation in sounds from six known or suspected species of fish across the three missions with depth consistently being the most significant factor. At the time and space scales of this study, there was no detectable effect of red tide on sound production. Sounds were still recorded within red tide-affected waters from species with overlapping depth ranges. These results suggest that the fishes studied here did not alter their sound production nor migrate out of red tide-affected areas. Although these results are preliminary because of the limited measurements, the data and methods presented here provide a proof of principle and could serve as protocol for future studies on the effects of algal blooms on the behavior of soniferous fishes. To fully capture the effects of episodic events, we suggest that stationary or vertically profiling acoustic recorders and environmental sampling be used as a complement to glider measurements.
PMCID: PMC4281131  PMID: 25551564
13.  Asymptomatic diabetes: screening by routine imaging beneficial? 
Netherlands Heart Journal  2014;23(2):79-81.
PMCID: PMC4315791  PMID: 25523512
14.  Biofilm growth mode promotes maximum carrying capacity and community stability during product inhibition syntrophy 
Sulfate-reducing bacteria (SRB) can interact syntrophically with other community members in the absence of sulfate, and interactions with hydrogen-consuming methanogens are beneficial when these archaea consume potentially inhibitory H2 produced by the SRB. A dual continuous culture approach was used to characterize population structure within a syntrophic biofilm formed by the SRB Desulfovibrio vulgaris Hildenborough and the methanogenic archaeum Methanococcus maripaludis. Under the tested conditions, monocultures of D. vulgaris formed thin, stable biofilms, but monoculture M. maripaludis did not. Microscopy of intact syntrophic biofilm confirmed that D. vulgaris formed a scaffold for the biofilm, while intermediate and steady-state images revealed that M. maripaludis joined the biofilm later, likely in response to H2 produced by the SRB. Close interactions in structured biofilm allowed efficient transfer of H2 to M. maripaludis, and H2 was only detected in cocultures with a mutant SRB that was deficient in biofilm formation (ΔpilA). M. maripaludis produced more carbohydrate (uronic acid, hexose, and pentose) as a monoculture compared to total coculture biofilm, and this suggested an altered carbon flux during syntrophy. The syntrophic biofilm was structured into ridges (∼300 × 50 μm) and models predicted lactate limitation at ∼50 μm biofilm depth. The biofilm had structure that likely facilitated mass transfer of H2 and lactate, yet maximized biomass with a more even population composition (number of each organism) when compared to the bulk-phase community. Total biomass protein was equivalent in lactate-limited and lactate-excess conditions when a biofilm was present, but in the absence of biofilm, total biomass protein was significantly reduced. The results suggest that multispecies biofilms create an environment conducive to resource sharing, resulting in increased biomass retention, or carrying capacity, for cooperative populations.
PMCID: PMC4266047  PMID: 25566209
anaerobic; carrying capacity; hydrogen transfer; population intermixing; sulfate-reducing bacteria
16.  The right ventricle: always normal in normal subjects? 
Netherlands Heart Journal  2014;23(1):62-63.
PMCID: PMC4268211  PMID: 25492108
19.  The latent structure and predictors of non-medical prescription drug use and prescription drug use disorders: a national study 
Drug and alcohol dependence  2013;133(2):10.1016/j.drugalcdep.2013.07.011.
Despite growing concerns about non-medical prescription drug use and prescription drug use disorders, whether vulnerability for these conditions is drug-specific or occurs through a shared liability and common risk factors is unknown.
Exploratory and confirmatory factor analysis of Wave 1 of the National Epidemiologic Survey on Alcohol and Related Conditions were used to examine the latent structure of non-medical prescription drug use and prescription drug use disorders. Multiple indicators multiple causes (MIMIC) analysis was used to examine whether the effect of sociodemographic and psychiatric covariates occurred through the latent factor, directly on each drug class or both.
A one-factor model described well the structure of both non-medical prescription drug use and prescription drug use disorders. Younger age, being White, having more intense pain or one of several psychiatric disorders increased the risk of non-medical prescription drug use through the latent factor. The same covariates, except for anxiety disorders also significantly increased the risk of prescription drug use disorders through the latent factor. Older age directly increased the risk of non-medical use of sedatives, and alcohol use disorders decreased the risk of non-medical tranquilizer use. No covariates had direct effects on the risk of any prescription drug use disorders beyond their effect through the latent factor.
The risk for non-medical prescription drug use and prescription drug use disorders occurs through a shared liability. Treatment, prevention and policy approaches directed at these drugs as a group maybe more effective than those focused on individual classes of drugs.
PMCID: PMC3818293  PMID: 23962421
Non-medical prescription drug use; Prescription Drug Use Disorders; Latent Structure; NESARC
20.  The muscle protein synthetic response to the combined ingestion of protein and carbohydrate is not impaired in healthy older men 
Age  2013;35(6):2389-2398.
Aging is associated with a progressive decline in skeletal muscle mass. It has been hypothesized that an attenuated muscle protein synthetic response to the main anabolic stimuli may contribute to the age-related loss of muscle tissue. The aim of the present study was to compare the muscle protein synthetic response following ingestion of a meal-like amount of dietary protein plus carbohydrate between healthy young and older men. Twelve young (21 ± 1 years) and 12 older (75 ± 1 years) men consumed 20 g of intrinsically l-[1-13C]phenylalanine-labeled protein with 40 g of carbohydrate. Ingestion of specifically produced intrinsically l-[1-13C]phenylalanine-labeled protein allowed us to assess the subsequent incorporation of casein-derived amino acids into muscle protein. Blood samples were collected at regular intervals, with muscle biopsies obtained prior to and 2 and 6 h after protein plus carbohydrate ingestion. The acute post-prandial rise in plasma glucose and insulin concentrations was significantly greater in the older compared with the younger males. Plasma amino acid concentrations increased rapidly following drink ingestion in both groups. However, plasma leucine concentrations were significantly lower at t = 90 min in the older when compared with the young group (P < 0.05). Muscle protein-bound l-[1-13C]phenylalanine enrichments increased to 0.0071 ± 0.0016 and 0.0072 ± 0.0013 mole percent excess (MPE) at 2 h and 0.0229 ± 0.0016 and 0.0213 ± 0.0024 MPE at 6 h following ingestion of the intrinsically labeled protein in the young and older males, respectively, with no differences between groups (P > 0.05). We conclude that the use of dietary protein-derived amino acids for muscle protein synthesis is not impaired in healthy older men following intake of protein plus carbohydrate.
PMCID: PMC3824983  PMID: 23529503
Skeletal muscle; Aging; Sarcopenia; Amino acids; Anabolic resistance
21.  The Implementation of Novel Collaborative Structures for the Identification and Resolution of Barriers to Pluripotent Stem Cell Translation 
Stem Cells and Development  2013;22(Suppl 1):63-72.
Increased global connectivity has catalyzed technological development in almost all industries, in part through the facilitation of novel collaborative structures. Notably, open innovation and crowd-sourcing—of expertise and/or funding—has tremendous potential to increase the efficiency with which biomedical ecosystems interact to deliver safe, efficacious and affordable therapies to patients. Consequently, such practices offer tremendous potential in advancing development of cellular therapies.
In this vein, the CASMI Translational Stem Cell Consortium (CTSCC) was formed to unite global thought-leaders, producing academically rigorous and commercially practicable solutions to a range of challenges in pluripotent stem cell translation. Critically, the CTSCC research agenda is defined through continuous consultation with its international funding and research partners.
Herein, initial findings for all research focus areas are presented to inform global product development strategies, and to stimulate continued industry interaction around biomanufacturing, strategic partnerships, standards, regulation and intellectual property and clinical adoption.
PMCID: PMC3883132  PMID: 24304079
22.  Phylogenetic Profiles of In-House Microflora in Drains at a Food Production Facility: Comparison and Biocontrol Implications of Listeria-Positive and -Negative Bacterial Populations 
Applied and Environmental Microbiology  2014;80(11):3369-3374.
Listeria species experience complex interactions with other microorganisms, which may promote growth and colonization of the organism in local environments or negatively affect them. This study investigated the microbial community at a food production facility, examining interactions between Listeria and the associated microbiome. Listeria species can be transferred between zones in the production environment by individuals or equipment, and drains may act as a reservoir for the organism, reflecting the microbial flora potentially in the production environment. Drains that were colonized by Listeria species and those determined to be free of Listeria were examined. In each case, 16S rRNA gene analysis was performed using the PhyloChip platform. Some general similarities in bacterial population structure were observed when Listeria-negative and -positive drain communities were compared, with some distinct differences also noted. These included increased populations of the genera Prevotella and Janthinobacterium associated with the absence of Listeria species, whereas Enterococcus and Rhodococcus were in higher abundance in drains colonized by Listeria species. Based on these results, a selection of bacterial species were grown in coculture biofilm with a Listeria monocytogenes strain identified as having colonized a drain at the facility. Mixed-species biofilm experiments showed that Janthinobacterium inhibited attachment and subsequent biofilm formation of L. monocytogenes; however, Enterococcus gallinarum significantly increased it. The results of this study suggest the microbial community in food processing facilities can impact the colonization of Listeria species and that influencing the microbiome in favor of antilisterial species may reduce the colonization of Listeria species and limit the likelihood of product/process contamination.
PMCID: PMC4018852  PMID: 24657862
23.  Adolescence to Young Adulthood: When Socio-economic Disparities in Substance Use Emerge 
Substance use & misuse  2013;48(14):1522-1529.
Our objective was to examine the longitudinal trends of substance use (cigarette, alcohol, and marijuana use) in a cohort of young people by participants’ eventual educational attainment. We aimed to pinpoint the life stages when the socioeconomic disparities in these behaviors emerge.
The analytic sample included 1,902 participants from Project EAT, a 10-year longitudinal study. Participants were assessed from early adolescence (middle school) through middle young adulthood (mid 20s) and categorized into groups of eventual educational attainment.
Generally, for cigarettes and marijuana, disparities were evident by early adolescence with prevalence of use highest among those who had no secondary education, followed by 2-year college and then 4-year college attendees/graduates. With alcohol, reported use tended to be similar during adolescence for all three education groups, but then diverged during young adulthood. At this stage the 4-year college group reported the most weekly alcohol use, but the no postsecondary education group reported the most daily use.
The points at which disparities in substance use behaviors first emerge and later escalate can offer guidance as to how to craft, and when to target, interventions and policies.
PMCID: PMC4060522  PMID: 23834465
smoking; alcohol; marijuana; young adulthood; adolescence; socio-economic status
24.  The Repeat Region of the Circumsporozoite Protein is Critical for Sporozoite Formation and Maturation in Plasmodium 
PLoS ONE  2014;9(12):e113923.
The circumsporozoite protein (CSP) is the major surface protein of the sporozoite stage of malaria parasites and has multiple functions as the parasite develops and then migrates from the mosquito midgut to the mammalian liver. The overall structure of CSP is conserved among Plasmodium species, consisting of a species-specific central tandem repeat region flanked by two conserved domains: the NH2-terminus and the thrombospondin repeat (TSR) at the COOH-terminus. Although the central repeat region is an immunodominant B-cell epitope and the basis of the only candidate malaria vaccine in Phase III clinical trials, little is known about its functional role(s). We used the rodent malaria model Plasmodium berghei to investigate the role of the CSP tandem repeat region during sporozoite development. Here we describe two mutant parasite lines, one lacking the tandem repeat region (ΔRep) and the other lacking the NH2-terminus as well as the repeat region (ΔNΔRep). We show that in both mutant lines oocyst formation is unaffected but sporozoite development is defective.
PMCID: PMC4250072  PMID: 25438048
25.  Suicidal ideation among surgeons in Italy and Sweden – a cross-sectional study 
BMC psychology  2014;2(1):53.
Suicidal ideation is more prevalent among physicians, compared to the population in general, but little is known about the factors behind surgeons’ suicidal ideation. A surgeon’s work environment can be competitive and characterised by degrading experiences, which could contribute to burnout, depression and even thoughts of suicide. Being a surgeon has been reported to be predictor for not seeking help when psychological distressed. The aim of the present study was to investigate to what extent surgeons in Italy and Sweden are affected by suicidal ideation, and how suicidal ideation can be associated with psychosocial work conditions.
A cross-sectional study of surgeons was performed in Italy (N = 149) and Sweden (N = 272), where having suicidal ideation was the outcome variable. Work-related factors, such as harassment, depression and social support, were also measured.
Suicidal ideation within the previous twelve months was affirmatively reported by 18% of the Italian surgeons, and by 12% of the Swedish surgeons in the present study. The strongest association with having recent suicidal ideation for both countries was being subjected to degrading experiences/harassment at work by a senior physician. Sickness presenteeism, exhaustion and disengagement were related to recent suicidal ideation among Italian surgeons, while role conflicts and sickness presenteeism were associated with recent suicidal ideation in the Swedish group. For both countries, regular meetings to discuss situations at work were found to be protective.
A high percentage of surgeons at two university hospitals in Italy and Sweden reported suicidal ideation during the year before the investigation. This reflects a tough workload, including sickness presenteeism, harassment at work, exhaustion/disengagement and role conflicts. Regular meetings to discuss work situations might be protective.
PMCID: PMC4266411  PMID: 25520811

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