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1.  Evidence for the role of German final devoicing in pre-attentive speech processing: a mismatch negativity study 
Frontiers in Psychology  2014;5:1317.
Results of a mismatch negativity experiment are reported in which the pre-attentive relevance of the German phonological alternation of final devoicing (FD) is shown in two ways. The experiment employs pseudowords. (1) A deviant [vus] paired with standard /vuzə/ did not show a mismatch effect for the voicing change in /z/ versus [s] because the two can be related by FD. When standard and deviant were reversed, the two could not be related by FD and a mismatch effect for the voicing difference occurred. (2) An ill-formed deviant that violates FD, *[vuz], triggered mismatch effects that were plausibly attributed to its ill-formedness. The results show that a syllable-related process like FD is already taken into account by the processing system in early pre-attentive processing.
PMCID: PMC4243496  PMID: 25505433
mismatch negativity (MMN); event-related potentials (ERP); phonological rules; final devoicing; phonotactics; German; pre-attentive processing
2.  Combined Treatment with a BACE Inhibitor and Anti-Aβ Antibody Gantenerumab Enhances Amyloid Reduction in APPLondon Mice 
The Journal of Neuroscience  2014;34(35):11621-11630.
Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer‘s disease. Among the agents explored in clinical trials are anti-Aβ peptide antibodies and secretase inhibitors. Most anti-Aβ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid, although secretase inhibitors reduce the de novo production of Aβ. Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment. We performed a chronic study in APPLondon transgenic mice that received treatment with anti-Aβ antibody gantenerumab and BACE inhibitor RO5508887, either as mono- or combination treatment. Treatment aimed to evaluate efficacy on amyloid progression, similar to preexisting amyloidosis as present in Alzheimer's disease patients. Mono-treatments with either compound caused a dose-dependent reduction of total brain Aβ and amyloid burden. Combination treatment with both compounds significantly enhanced the antiamyloid effect. The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number, which suggests effective inhibition of de novo plaque formation. Moreover, significantly enhanced clearance of pre-existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887. BACE inhibition led to a significant time- and dose-dependent decrease in CSF Aβ, which was not observed for gantenerumab treatment. Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance.
PMCID: PMC4145168  PMID: 25164658
Aβ-antibody; Alzheimer's disease; amyloidosis; BACE; tg-APP mouse
3.  Clinical phenotype associations with various types of anti-dsDNA antibodies in patients with recent onset of rheumatic symptoms. Results from a multicentre observational study 
Lupus Science & Medicine  2014;1(1):e000007.
Despite anti-dsDNA antibodies constitute a wide range of specificities, they are considered as the hallmark for systemic lupus erythematosus (SLE).
To identify clinical phenotypes associated with anti-dsDNA antibodies, independently of any clinical diagnoses.
Patients with recent onset of any rheumatic symptoms were screened for antinuclear antibodies (ANA). All ANA-positive and matching ANA-negative patients were examined, and their clinical phenotypes were registered, using a systematic chart formulated after consensus between the participating centres. All patients were tested for different anti-dsDNA antibody specificities with assays habitually used in each participating laboratory. Crithidia Luciliae Immuno Fluorescence Test (CLIFT) was performed three times (with two different commercial kits); solid and solution phase ELISA were performed four times. Associations between clinical phenotypes and results of anti-dsDNA assays were evaluated by linear regression analysis (LRA) and principal component analysis (PCA).
Totally, 292 ANA-positive and 292 matching ANA-negative patients were included in the study. A full dataset for statistical analysis was obtained in 547 patients. Anti-dsDNA antibodies were most frequently detected by ELISA. LRA showed that overall positivity of anti-dsDNA antibodies was associated with proteinuria and pleuritis. Alopecia was significantly associated only with CLIFT-positivity. Besides confirming the same findings, PCA showed that combined positivity of CLIFT and ELISA was also associated with lymphopenia.
Our results show that different anti-dsDNA antibody specificities are associated with nephropathy, pleuritis, alopecia and lymphopenia, regardless of the diagnosis. It may challenge the importance of anti-dsDNA antibodies as a diagnostic hallmark for SLE.
PMCID: PMC4225731  PMID: 25396058
Autoantibodies; Autoimmunity; Systemic Lupus Erythematosus; Lupus Nephritis; Autoimmune Diseases
4.  Interobserver agreement for the spine instability neoplastic score varies according to the experience of the evaluator 
Clinics  2013;68(2):213-217.
To evaluate the interobserver agreement for the Neoplastic Spine Instability Score (SINS) among spine surgeons with or without experience in vertebral metastasis treatment and physicians in other specialties.
Case descriptions were produced based on the medical records of 40 patients with vertebral metastases. The descriptions were then published online. Physicians were invited to evaluate the descriptions by answering questions according to the Neoplastic Spine Instability Score (SINS). The agreement among physicians was calculated using the kappa coefficient.
Seventeen physicians agreed to participate: three highly experienced spine surgeons, seven less-experienced spine surgeons, three surgeons of other specialties, and four general practitioners (n = 17). The agreement for the final SINS score among all participants was fair, and it varied according to the SINS component. The agreement was substantial for the spine location only. The agreement was higher among experienced surgeons. The agreement was nearly perfect for spinal location among the spine surgeons who were highly experienced in vertebral metastases.
This study demonstrates that the experience of the evaluator has an impact on SINS scale classification. The interobserver agreement was only fair among physicians who were not spine surgeons and among spine surgeons who were not experienced in the treatment of vertebral metastases, which may limit the use of the SINS scale for the screening of unstable lesions by less-experienced evaluators.
PMCID: PMC3584270  PMID: 23525318
Spine; Health Services Research; Models, Statistical; Observer Variation
5.  Transport and Distribution of Salmonella enterica Serovar Typhimurium in Loamy and Sandy Soil Monoliths with Applied Liquid Manure ▿  
A leaching experiment, where liquid manure spiked with Salmonella enterica serovar Typhimurium (Tet+) DSM554 was applied to soil surfaces, was conducted on intact soil monoliths (60 cm in diameter and 100 cm long). A total of 6.5 × 1010 CFU was applied to each column. We found that Salmonella serovar Typhimurium could be transported to a 1-m depth in loamy soil at concentrations reaching 1.3 × 105 CFU/ml of leachate. The test strain was found in concentrations ranging from 300 to 1.35 cells/ml in loamy soil throughout the 27 days of the experiment, while concentrations below 20 cells/ml were sporadically detected in the leachates from sandy monoliths. Real-time PCR targeting invA DNA showed a clear correspondence between the total and culturable numbers of cells in the leachate, indicating that most cells leached were viable. On day 28, distribution of Salmonella serovar Typhimurium at five depths in the four monoliths was determined. The highest recovery rate, ranging from 1.5% to 3.8% of the total applied inoculum, was found in the top 0.2 m.
PMCID: PMC2813018  PMID: 20023094
6.  Elucidating the Key Member of a Linuron-Mineralizing Bacterial Community by PCR and Reverse Transcription-PCR Denaturing Gradient Gel Electrophoresis 16S rRNA Gene Fingerprinting and Cultivation 
A bacterial community from Danish agricultural soil was enriched with linuron [N-(3,4-dichlorophenyl)-N′-methoxy-N′-methylurea] as the sole carbon and nitrogen source. The community mineralized [ring-U-14C]linuron completely to 14CO2 and 14C-biomass. Denaturing gradient gel electrophoresis analysis and cultivation revealed that a Variovorax sp. was responsible for the mineralization activity.
PMCID: PMC1169018  PMID: 16000836
7.  Tumor necrosis factor-alpha inhibits stem cell factor-induced proliferation of human bone marrow progenitor cells in vitro. Role of p55 and p75 tumor necrosis factor receptors. 
Journal of Clinical Investigation  1994;94(1):165-172.
Stem cell factor (SCF), a key regulator of hematopoiesis, potently synergizes with a number of hematopoietic growth factors. However, little is known about growth factors capable of inhibiting the actions of SCF. TNF-alpha has been shown to act as a bidirectional regulator of myeloid cell proliferation and differentiation. This study was designed to examine interactions between TNF-alpha and SCF. Here, we demonstrate that TNF-alpha potently and directly inhibits SCF-stimulated proliferation of CD34+ hematopoietic progenitor cells. Furthermore, TNF-alpha blocked all colony formation stimulated by SCF in combination with granulocyte colony-stimulating factor (CSF) or CSF-1. The synergistic effect of SCF observed in combination with GM-CSF or IL-3 was also inhibited by TNF-alpha, resulting in colony numbers similar to those obtained in the absence of SCF. These effects of TNF-alpha were mediated through the p55 TNF receptor, whereas little or no inhibition was signaled through the p75 TNF receptor. Finally, TNF-alpha downregulated c-kit cell-surface expression on CD34+ bone marrow cells, and this was predominantly a p55 TNF receptor-mediated event as well.
PMCID: PMC296294  PMID: 7518828
8.  Ethanol Reassimilation and Ethanol Tolerance in Pichia stipitis CBS 6054 as Studied by 13C Nuclear Magnetic Resonance Spectroscopy 
Ethanol reassimilation in Pichia stipitis CBS 6054 was studied by using continuous cultures, and the oxidation of [1-13C]ethanol was monitored by in vivo and in vitro 13C nuclear magnetic resonance spectroscopy. Acetate was formed when ethanol was reassimilated. The ATP/ADP ratio and the carbon dioxide production decreased, whereas the malate dehydrogenase activity increased, in ethanol-reassimilating cells. The results are discussed in terms of the low ethanol tolerance in P. stipitis compared with that in Saccharomyces cerevisiae (S. W. Brown, S. G. Oliver, D. E. F. Harrison, and R. C. Righelato, Eur. J. Appl. Microbiol. Biotechnol. 11:151-155, 1981).
PMCID: PMC195820  PMID: 16348754
9.  Attitudes toward home-based malaria testing in rural and urban Sierra Leone 
Malaria Journal  2015;14:80.
The purpose of this study was to examine malaria testing practices and preferences in Bo, Sierra Leone, and to ascertain interest in and willingness to take a home-based rapid diagnostic test administered by a community health volunteer (CHV) or a trained family member rather than travelling to a clinical facility for laboratory-based testing.
A population-based, cross-sectional survey of 667 randomly-sampled rural households and 157 urban households was conducted in December 2013 and January 2014.
Among rural residents, 69% preferred a self/family- or CHV-conducted home-based malaria test and 20% preferred a laboratory-based test (with others indicating no preference). Among urban residents, these numbers were 38% and 44%, respectively. If offered a home-based test, 28% of rural residents would prefer a self/family-conducted test and 68% would prefer a CHV-assisted test. For urban residents, these numbers were 21% and 77%. In total, 36% of rural and 63% of urban residents reported usually taking a diagnostic test to confirm suspected malaria. The most common reasons for not seeking malaria testing were the cost of testing, waiting to see if the fever resolved on its own, and not wanting to travel to a clinical facility for a test. In total, 32% of rural and 27% of urban participants were very confident they could perform a malaria test on themselves or a family member without assistance, 50% of rural and 62% of urban participants were very confident they could perform a test after training, and 56% of rural and 33% of urban participants said they would pay more for a home-based test than a laboratory-based test.
Expanding community case management of malaria to include home testing by CHVs and family members may increase the proportion of individuals with febrile illnesses who confirm a positive diagnosis prior to initiating treatment.
PMCID: PMC4334841
Malaria; Rapid diagnostic test; Diagnostic test kits; Community health services; Community health worker; Sierra Leone; West Africa
Growing awareness of health and health care disparities highlights the importance of including information about race, ethnicity, and culture (REC) in health research. Reporting of REC factors in research publications, however, is notoriously imprecise and unsystematic. This article describes the development of a checklist to assess the comprehensiveness and the applicability of REC factor reporting in psychiatric research publications. The 16-itemGAP-REACH© checklist was developed through a rigorous process of expert consensus, empirical content analysis in a sample of publications (N = 1205), and interrater reliability (IRR) assessment (N = 30). The items assess each section in the conventional structure of a health research article. Data from the assessment may be considered on an item-by-item basis or as a total score ranging from 0% to 100%. The final checklist has excellent IRR (κ = 0.91). The GAP-REACH may be used by multiple research stakeholders to assess the scope of REC reporting in a research article.
PMCID: PMC4324559  PMID: 24080673
Race; ethnicity; culture; checklist; psychiatric literature
11.  Cerebral 5-HT2A receptor binding, but not mGluR2, is increased in tryptophan hydroxylase 2 decrease-of-function mice 
Neuroscience letters  2013;555:118-122.
Transgenic mice with knock-in (KI) of a tryptophan hydroxylase 2 (Tph2) R439H mutation, analogous to the Tph2 R441H single-nucleotide polymorphism originally identified in a late life depression cohort, have markedly reduced levels of 5-hydroxytryptamine (5-HT). These Tph2KI mice are therefore interesting as a putative translational model of low endogenous 5-HT function that allows for assessment of adaptive changes in different anatomical regions. Here, we determined 5-HT2A receptor binding in several brain regions using in vitro receptor autoradiography and two different radioligands. When using the 5-HT2A receptor selective antagonist radioligand 3H-MDL100907, we found higher binding in the prefrontal cortex (10%, P=0.009), the striatum (26%, P=0.005), and the substantia nigra (21%, P=0.027). The increase was confirmed in the same regions with the 5-HT2A/C receptor agonist, 3H-CIMBI-36 (2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine). 5-HT2A receptors establish heteromeric functional receptor complexes with metabotropic glutamate 2 receptors (mGluR2), but binding levels of the mGluR2/3 ligand 3H-LY341495 were unaltered in brain areas with increased 5-HT2A receptor levels. These data show that in distinct anatomical regions, 5-HT2A receptor binding sites are up-regulated in 5-HT deficient mice, and this increase is not associated with changes in mGluR2 binding.
PMCID: PMC4323164  PMID: 24055299
12.  Protective Effects of Transforming Growth Factor β2 in Intestinal Epithelial Cells by Regulation of Proteins Associated with Stress and Endotoxin Responses 
PLoS ONE  2015;10(2):e0117608.
Transforming growth factor (TGF)-β2 is an important anti-inflammatory protein in milk and colostrum. TGF-β2 supplementation appears to reduce gut inflammatory diseases in early life, such as necrotizing enterocolitis (NEC) in young mice. However, the molecular mechanisms by which TGF-β2 protects immature intestinal epithelial cells (IECs) remain to be more clearly elucidated before interventions in infants can be considered. Porcine IECs PsIc1 were treated with TGF-β2 and/or lipopolysaccharide (LPS), and changes in the cellular proteome were subsequently analyzed using two-dimensional gel electrophoresis-MS and LC-MS-based proteomics. TGF-β2 alone induced the differential expression of 13 proteins and the majority of the identified proteins were associated with stress responses, TGF-β and Toll-like receptor 4 signaling cascades. In particular, a series of heat shock proteins had similar differential trends as previously shown in the intestine of NEC-resistant preterm pigs and young mice. Furthermore, LC-MS-based proteomics and Western blot analyses revealed 20 differentially expressed proteins following treatment with TGF-β2 in LPS-challenged IECs. Thirteen of these proteins were associated with stress response pathways, among which five proteins were altered by LPS and restored by TGF-β2, whereas six were differentially expressed only by TGF-β2 in LPS-challenged IECs. Based on previously reported biological functions, these patterns indicate the anti-stress and anti-inflammatory effects of TGF-β2 in IECs. We conclude that TGF-β2 of dietary or endogenous origin may regulate the IEC responses against LPS stimuli, thereby supporting cellular homeostasis and innate immunity in response to bacterial colonization, and the first enteral feeding in early life.
PMCID: PMC4323210  PMID: 25668313
13.  Distinct Roles of Candida albicans-Specific Genes in Host-Pathogen Interactions 
Eukaryotic Cell  2014;13(8):977-989.
Human fungal pathogens are distributed throughout their kingdom, suggesting that pathogenic potential evolved independently. Candida albicans is the most virulent member of the CUG clade of yeasts and a common cause of both superficial and invasive infections. We therefore hypothesized that C. albicans possesses distinct pathogenicity mechanisms. In silico genome subtraction and comparative transcriptional analysis identified a total of 65 C. albicans-specific genes (ASGs) expressed during infection. Phenotypic characterization of six ASG-null mutants demonstrated that these genes are dispensable for in vitro growth but play defined roles in host-pathogen interactions. Based on these analyses, we investigated two ASGs in greater detail. An orf19.6688Δ mutant was found to be fully virulent in a mouse model of disseminated candidiasis and to induce higher levels of the proinflammatory cytokine interleukin-1β (IL-1β) following incubation with murine macrophages. A pga16Δ mutant, on the other hand, exhibited attenuated virulence. Moreover, we provide evidence that secondary filamentation events (multiple hyphae emerging from a mother cell and hyphal branching) contribute to pathogenicity: PGA16 deletion did not influence primary hypha formation or extension following contact with epithelial cells; however, multiple hyphae and hyphal branching were strongly reduced. Significantly, these hyphae failed to damage host cells as effectively as the multiple hypha structures formed by wild-type C. albicans cells. Together, our data show that species-specific genes of a eukaryotic pathogen can play important roles in pathogenicity.
PMCID: PMC4135803  PMID: 24610660
14.  Time-Dependent Subcellular Distribution and Effects of Carbon Nanotubes in Lungs of Mice 
PLoS ONE  2015;10(1):e0116481.
Background and Methods
Pulmonary deposited carbon nanotubes (CNTs) are cleared very slowly from the lung, but there is limited information on how CNTs interact with the lung tissue over time. To address this, three different multiwalled CNTs were intratracheally instilled into female C57BL/6 mice: one short (850 nm) and tangled, and two longer (4 μm and 5.7 μm) and thicker. We assessed the cellular interaction with these CNTs using transmission electron microscopy (TEM) 1, 3 and 28 days after instillation.
TEM analysis revealed that the three CNTs followed the same overall progression pattern over time. Initially, CNTs were taken up either by a diffusion mechanism or via endocytosis. Then CNTs were agglomerated in vesicles in macrophages. Lastly, at 28 days post-exposure, evidence suggesting CNT escape from vesicle enclosures were found. The longer and thicker CNTs more often perturbed and escaped vesicular enclosures in macrophages compared to the smaller CNTs. Bronchoalveolar lavage (BAL) showed that the CNT exposure induced both an eosinophil influx and also eosinophilic crystalline pneumonia.
Two very different types of multiwalled CNTs had very similar pattern of cellular interactions in lung tissue, with the longer and thicker CNTs resulting in more severe effects in terms of eosinophil influx and incidence of eosinophilic crystalline pneumonia (ECP).
PMCID: PMC4304811  PMID: 25615613
15.  The consequences of balanced harvesting of fish communities 
Balanced harvesting, where species or individuals are exploited in accordance with their productivity, has been proposed as a way to minimize the effects of fishing on marine fish communities and ecosystems. This calls for a thorough examination of the consequences balanced harvesting has on fish community structure and yield. We use a size- and trait-based model that resolves individual interactions through competition and predation to compare balanced harvesting with traditional selective harvesting, which protects juvenile fish from fishing. Four different exploitation patterns, generated by combining selective or unselective harvesting with balanced or unbalanced fishing, are compared. We find that unselective balanced fishing, where individuals are exploited in proportion to their productivity, produces a slightly larger total maximum sustainable yield than the other exploitation patterns and, for a given yield, the least change in the relative biomass composition of the fish community. Because fishing reduces competition, predation and cannibalism within the community, the total maximum sustainable yield is achieved at high exploitation rates. The yield from unselective balanced fishing is dominated by small individuals, whereas selective fishing produces a much higher proportion of large individuals in the yield. Although unselective balanced fishing is predicted to produce the highest total maximum sustainable yield and the lowest impact on trophic structure, it is effectively a fishery predominantly targeting small forage fish.
PMCID: PMC3866413  PMID: 24307676
balanced harvesting; size spectrum; selective fisheries; ecosystem-based fisheries management; maximum sustainable yield
16.  Conducted Vasoreactivity: the Dynamical Point of View 
Conducted vasodilation is part of the physiological response to increasing metabolic demand of the tissue. Similar responses can be elicited by focal electrical or chemical stimulation. Some evidence suggests an endothelial pathway for nondecremental transmission of hyperpolarizing pulses. However, the underlying mechanisms are debated. Here, we focus on dynamical aspects of the problem hypothesizing the existence of a bistability-powered mechanism for regenerative pulse transmission along the endothelium. Bistability implies that the cell can have two different stable resting potentials and can switch between those states following an appropriate stimulus. Bistability is possible if the current–voltage curve is N shaped instead of monotonically increasing. Specifically, the presence of an inwardly rectifying potassium current may provide the endothelial cell with such properties. We provide a theoretical analysis as well as numerical simulations of both single- and multiunit bistable systems mimicking endothelial cells to investigate the self-consistence and stability of the proposed mechanism. We find that the individual cell may switch readily between two stable potentials. An array of coupled cells, however, as found in the vascular wall, requires a certain adaptation of the membrane currents after a switch, in order to switch back. Although the formulation is generic, we suggest a combination of specific membrane currents that could underlie the phenomenon.
PMCID: PMC4303742  PMID: 25583354
Endothelial cell; Conducted vasodilation; Membrane potential; Bistability
17.  Evaluation of Aminohydantoins as a Novel Class of Antimalarial Agents 
Given the threat of drug resistance, there is an acute need for new classes of antimalarial agents that act via a unique mechanism of action relative to currently used drugs. We have identified a set of druglike compounds within the Tres Cantos Anti-Malarial Set (TCAMS) which likely act via inhibition of a Plasmodium aspartic protease. Structure–activity relationship analysis and optimization of these aminohydantoins demonstrate that these compounds are potent nanomolar inhibitors of the Plasmodium aspartic proteases PM-II and PM-IV and likely one or more other Plasmodium aspartic proteases. Incorporation of a bulky group, such as a cyclohexyl group, on the aminohydantion N-3 position gives enhanced antimalarial potency while reducing inhibition of human aspartic proteases such as BACE. We have identified compound 8p (CWHM-117) as a promising lead for optimization as an antimalarial drug with a low molecular weight, modest lipophilicity, oral bioavailability, and in vivo antimalarial activity in mice.
PMCID: PMC4027786  PMID: 24900778
Malaria; antimalarial; aminohydantoin; medicinal chemistry; aspartic protease inhibitors
19.  Chiral sulfinamidourea/Strong Brønsted Acid co-catalyzed enantioselective Povarov reaction to access tetrahydroquinolines 
Nature protocols  2014;9(8):1860-1866.
This protocol describes a method for the laboratory synthesis of chiral tetrahydroisoquinolines, bicyclic organic framework present in a wide assortment of natural and synthetic biologically important compounds. The methodology involves the use of a two-catalyst system: an achiral strong Brønsted acid, together with a chiral urea derivative. The anion-binding properties of the urea lead to association of the ion pair that results from protonation of the imine substrate. Cycloaddition with electron-rich olefins in a [4+2] pathway, followed by spontaneous proton loss and rearomatization leads to the tetrahydroisoquinoline products in highly enantioenriched form.
PMCID: PMC4284825  PMID: 25010906
20.  Asymmetric Ion-Pairing Catalysis 
Charged intermediates and reagents are ubiquitous in organic transformations. The interaction of these ionic species with chiral neutral, anionic, or cationic small molecules has emerged as a powerful strategy for catalytic, enantioselective synthesis. This review describes developments in the burgeoning field of asymmetric ion-pairing catalysis with an emphasis on the insights that have been gleaned into the structural and mechanistic features that contribute to high asymmetric induction.
PMCID: PMC4284951  PMID: 23192886
anion-binding catalysis; asymmetric catalysis; chiral anions; ion pairs; phase-transfer catalysis
21.  Photoredox Activation and Anion Binding Catalysis in the Dual Catalytic Enantioselective Synthesis of β-Amino Esters 
The enantioselective oxidative C-H functionalization of tetrahydroisoquinoline derivatives is achieved through the merger of photoredox and asymmetric anion-binding catalysis. This combination of two distinct catalysis concepts introduces a potentially general approach to asymmetric transformations in oxidative photocatalysis.
PMCID: PMC3842187  PMID: 24294480
22.  Alignment of low-dose X-ray fluorescence tomography images using differential phase contrast 
Journal of Synchrotron Radiation  2013;21(Pt 1):229-234.
Differential phase contrast images acquired simultaneously with fluorescence images offer a robust method for alignment in low-dose X-ray nanotomography data acquisition.
X-ray fluorescence nanotomography provides unprecedented sensitivity for studies of trace metal distributions in whole biological cells. Dose fractionation, in which one acquires very low dose individual projections and then obtains high statistics reconstructions as signal from a voxel is brought together (Hegerl & Hoppe, 1976 ▶), requires accurate alignment of these individual projections so as to correct for rotation stage runout. It is shown here that differential phase contrast at 10.2 keV beam energy offers the potential for accurate cross-correlation alignment of successive projections, by demonstrating that successive low dose, 3 ms per pixel, images acquired at the same specimen position and rotation angle have a narrower and smoother cross-correlation function (1.5 pixels FWHM at 300 nm pixel size) than that obtained from zinc fluorescence images (25 pixels FWHM). The differential phase contrast alignment resolution is thus well below the 700 nm × 500 nm beam spot size used in this demonstration, so that dose fractionation should be possible for reduced-dose, more rapidly acquired, fluorescence nanotomography experiments.
PMCID: PMC3874022  PMID: 24365941
X-ray fluorescence tomography; differential phase contrast
23.  Lymphoma risk in systemic lupus: effects of disease activity versus treatment 
Annals of the rheumatic diseases  2013;73(1):10.1136/annrheumdis-2012-202099.
To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE).
We performed case–cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated in regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarial drugs, glucocorticoids) demographics, calendar year, Sjogren’s syndrome, SLE duration and disease activity. We used adjusted mean SLE Disease Activity Index scores (SLEDAI-2K) over time, and drugs were treated both categorically (ever/never) and as estimated cumulative doses.
We studied 75 patients with lymphoma (72 non-Hodgkin, three Hodgkin) and 4961 cancer-free controls. Most lymphomas were of B-cell origin. As is seen in the general population, lymphoma risk in SLE was higher in male than female patients and increased with age. Lymphomas occurred a mean of 12.4 years (median 10.9) after SLE diagnosis. Unadjusted and adjusted analyses failed to show a clear association of disease activity with lymphoma risk. There was a suggestion of greater exposure to cyclophosphamide and to higher cumulative steroids in lymphoma cases than the cancer-free controls.
In this large SLE sample, there was a suggestion of higher lymphoma risk with exposure to cyclophosphamide and high cumulative steroids. Disease activity itself was not clearly associated with lymphoma risk. Further work will focus on genetic profiles that might interact with medication exposure to influence lymphoma risk in SLE.
PMCID: PMC3855611  PMID: 23303389
24.  Racial Differences in Longitudinal Changes in Serum Prostate-Specific Antigen Levels: The Olmsted County Study and The Flint Men’s Health Study 
Urology  2013;83(1):88-93.
To determine the distribution of and racial differences in changes in PSA from a population-based sample of men.
Materials and Methods
Data from two prospective cohort studies of a random sample of Caucasian men, ages 40–79 in 1990, followed biennially through 2007 and African-American men, ages 40–79 in 1996, followed through 2000 were examined to assess longitudinal changes in PSA concentrations. Serum PSA levels were determined at each examination for both cohorts and observations after a diagnosis of prostate cancer or treatment for benign prostatic hyperplasia (BPH) were censored. Observed and estimated annual percentage change in serum PSA levels were examined by race.
At baseline, the median PSA level in Caucasian men did not differ from the median level observed in African-American men (Caucasian men: 0.9 ng/mL; African-American men: 0.9 ng/mL; P value=0.48). However, African-American men had a much more rapid increase in PSA level over time compared to Caucasian men (median annual percent change in PSA Caucasian men: 3.6%/year; African-American men: 7.9%/year; P value<0.001).
These data suggest that African-American men have more rapid rates of change in PSA levels over time. If the difference in rate of changes between African-American and Caucasian men is an early indicator of future prostate cancer diagnosis, earlier detection in African-American men could help to alleviate the racial disparities in prostate cancer diagnosis and mortality.
PMCID: PMC3896508  PMID: 24139354
Prostate cancer; PSA; racial differences; epidemiology
25.  Epidermal Growth Factor Receptor Targeted Nuclear Delivery and High Resolution Whole Cell X-Ray Imaging of Fe3O4@TiO2 Nanoparticles in Cancer Cells 
ACS nano  2013;7(12):10502-10517.
Sequestration within the cytoplasm often limits the efficacy of therapeutic nanoparticles that have specific subcellular targets. To allow for both cellular and subcellular nanoparticle delivery we have created Epidermal Growth Factor Receptor (EGFR) targeted Fe3O4@TiO2 nanoparticles that use the native intracellular trafficking of EGFR to improve internalization and nuclear translocation in EGFR-expressing HeLa cells. While bound to EGFR these nanoparticles do not interfere with the interaction between EGFR and karyopherin-β, a protein that is critical for the translocation of ligand-bound EGFR to the nucleus. Thus, a portion of the EGFR targeted nanoparticles taken up by the cells also reaches cell nuclei. We were able to track nanoparticle accumulation in cells by flow cytometry and nanoparticle subcellular distribution by confocal fluorescent microscopy indirectly, using fluorescently labeled nanoparticles. More importantly, we imaged and quantified intracellular nanoparticles directly, by their elemental signatures, using X-ray fluorescence microscopy at the Bionanoprobe, the first instrument of its kind in the world. The Bionanoprobe can focus hard X-rays down to a 30 nm spot size to map the positions of chemical elements tomographically within whole frozen-hydrated cells. Finally, we show that photoactivation of targeted nanoparticles in cell nuclei, dependent on successful EGFR nuclear accumulation, induces significantly more double-stranded DNA breaks then photoactivation of nanoparticles that remain exclusively in the cytoplasm.
PMCID: PMC3919441  PMID: 24219664
nanoparticles; titanium dioxide; photoactivation; X-ray fluorescence microscopy; Epidermal Growth Factor Receptor

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