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1.  Resistance in the Rectal Carriage of Men in an Active Surveillance Cohort: Longitudinal Analysis 
The Journal of urology  2014;193(2):552-556.
Purpose
Rectal swabs can identify men with fluoroquinolone resistant bacteria and decrease the infection rate after transrectal ultrasound guided prostate biopsy by targeted antimicrobial prophylaxis. We evaluated the rate of fluoroquinolone resistance in an active surveillance cohort with attention to factors associated with resistance and changes in resistance with time.
Materials and Methods
We evaluated 416 men with prostate cancer on active surveillance who underwent rectal swabs to assess the rate of fluoroquinolone resistance compared to that in men undergoing diagnostic transrectal ultrasound guided prostate biopsy. The chi-square test and Student t-test were used to compare categorical and continuous variables, respectively. Poisson regression analysis was used for multivariate analysis.
Results
On the initial swab fluoroquinolone resistance was found in 95 of 416 men (22.8%) on active surveillance compared to 54 of 221 (24.4%) in the diagnostic biopsy cohort (p = 0.675). Diabetes was found in 4.0% of the fluoroquinolone sensitive group vs 14.7% of the resistant group (p <0.001). Biopsy history was not associated with resistance. Of those with a resistant first swab 62.9% had a resistant second swab and 88.9% of those with 2 resistant swabs showed resistance on the third swab. Of men with a sensitive first swab 10.6% showed resistance on the second swab and 10.6% of those with 2 sensitive swabs had resistant third swabs.
Conclusions
One of 4 men who present for surveillance and diagnostic trans-rectal ultrasound guided prostate biopsy have rectal flora resistant to fluooquinolone. Resistance is significantly associated with diabetes but the number of prior biopsies is not. Men with fluoroquinolone resistant flora tend to remain resistant with time.
doi:10.1016/j.juro.2014.08.008
PMCID: PMC4332776  PMID: 25111911
prostatic neoplasms; biopsy; fluoroquinolones; drug resistance; bacterial; diabetes mellitus
2.  A genomic classifier predicting metastatic disease progression in men with biochemical recurrence after prostatectomy 
BACKGROUND
Due to their varied outcomes, men with biochemical recurrence (BCR) following radical prostatectomy (RP) present a management dilemma. Here, we evaluate Decipher, a genomic classifier (GC), for its ability to predict metastasis following BCR.
METHODS
The study population included 85 clinically high-risk patients who developed BCR after RP. Time-dependent receiver operating characteristic (ROC) curves, weighted Cox proportional hazard models and decision curves were used to compare GC scores to Gleason score (GS), PSA doubling time (PSAdT), time to BCR (ttBCR), the Stephenson nomogram and CAPRA-S for predicting metastatic disease progression. All tests were two-sided with a type I error probability of 5%.
RESULTS
GC scores stratified men with BCR into those who would or would not develop metastasis (8% of patients with low versus 40% with high scores developed metastasis, P<0.001). The area under the curve for predicting metastasis after BCR was 0.82 (95% CI, 0.76–0.86) for GC, compared to GS 0.64 (0.58–0.70), PSAdT 0.69 (0.61–0.77) and ttBCR 0.52 (0.46–0.59). Decision curve analysis showed that GC scores had a higher overall net benefit compared to models based solely on clinicopathologic features. In multivariable modeling with clinicopathologic variables, GC score was the only significant predictor of metastasis (P = 0.003).
CONCLUSIONS
When compared to clinicopathologic variables, GC better predicted metastatic progression among this cohort of men with BCR following RP. While confirmatory studies are needed, these results suggest that use of GC may allow for better selection of men requiring earlier initiation of treatment at the time of BCR.
doi:10.1038/pcan.2013.49
PMCID: PMC4332821  PMID: 24145624
biochemical recurrence; genomic classifier; prognostic models; metastasis; clinical validation
3.  Retrospective review using targeted deep sequencing reveals mutational differences between gastroesophageal junction and gastric carcinomas 
BMC Cancer  2015;15:32.
Background
Adenocarcinomas of both the gastroesophageal junction and stomach are molecularly complex, but differ with respect to epidemiology, etiology and survival. There are few data directly comparing the frequencies of single nucleotide mutations in cancer-related genes between the two sites. Sequencing of targeted gene panels may be useful in uncovering multiple genomic aberrations using a single test.
Methods
DNA from 92 gastroesophageal junction and 75 gastric adenocarcinoma resection specimens was extracted from formalin-fixed paraffin-embedded tissue. Targeted deep sequencing of 46 cancer-related genes was performed through emulsion PCR followed by semiconductor-based sequencing. Gastroesophageal junction and gastric carcinomas were contrasted with respect to mutational profiles, immunohistochemistry and in situ hybridization, as well as corresponding clinicopathologic data.
Results
Gastroesophageal junction carcinomas were associated with younger age, more frequent intestinal-type histology, more frequent p53 overexpression, and worse disease-free survival on multivariable analysis. Among all cases, 145 mutations were detected in 31 genes. TP53 mutations were the most common abnormality detected, and were more common in gastroesophageal junction carcinomas (42% vs. 27%, p = 0.036). Mutations in the Wnt pathway components APC and CTNNB1 were more common among gastric carcinomas (16% vs. 3%, p = 0.006), and gastric carcinomas were more likely to have ≥3 driver mutations detected (11% vs. 2%, p = 0.044). Twenty percent of cases had potentially actionable mutations identified. R132H and R132C missense mutations in the IDH1 gene were observed, and are the first reported mutations of their kind in gastric carcinoma.
Conclusions
Panel sequencing of routine pathology material can yield mutational information on several driver genes, including some for which targeted therapies are available. Differing rates of mutations and clinicopathologic differences support a distinction between adenocarcinomas that arise in the gastroesophageal junction and those that arise in the stomach proper.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1021-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1021-7
PMCID: PMC4322811  PMID: 25656989
Gastric cancer; Gastroesophageal junction cancer; Gastric cancer genomics; Gastric cancer sequencing
4.  Improved Fronto-Parietal White Matter Integrity in Overweight Children is Associated with Attendance in an After-School Exercise Program 
Developmental neuroscience  2014;36(1):1-9.
Aerobic fitness is associated with white matter integrity (WMI) in adults as measured by diffusion tensor imaging (DTI). This study examined the effect of an 8-month exercise intervention on WMI in children. Participants were 18 sedentary, overweight (body mass index ≥ 85th percentile) 8- to 11-year-old children (94% Black), randomly assigned to either an aerobic exercise (n=10) or sedentary attention control group (n=8). Each group was offered an instructor-led after-school program every school day for approximately 8 months. Before and after the program, all subjects participated in DTI scans. Tractography was conducted to isolate the superior longitudinal fasciculus and investigate whether the exercise intervention affected WMI in this region. There was no group by time interaction for WMI in the superior longitudinal fasciculus. There was a group by time by attendance interaction, however, such that higher attendance at the exercise intervention, but not the control intervention, was associated with increased WMI. Heart rate and the total dose of exercise correlated with WMI changes in the exercise group. In the overall sample, increased WMI was associated with improved scores on a measure of attention and improved teacher ratings of executive function. This study indicates that participating in an exercise intervention improves WMI in children as compared to a sedentary after-school program.
doi:10.1159/000356219
PMCID: PMC3995327  PMID: 24457421
aerobic exercise; children; cognition; cognitive control; diffusion tensor imaging; overweight; superior longitudinal fasciculus
5.  An Eight Month Randomized Controlled Exercise Intervention Alters Resting State Synchrony in Overweight Children 
Neuroscience  2013;256:445-455.
Children with low aerobic fitness have altered brain function compared to higher-fit children. This study examined the effect of an 8-month exercise intervention on resting state synchrony. Twenty-two sedentary, overweight (body mass index ≥ 85th percentile) children 8–11 years old were randomly assigned to one of two after-school programs: aerobic exercise (n=13) or sedentary attention control (n=9). Before and after the 8-month programs, all subjects participated in resting state functional magnetic resonance imaging scans. Independent components analysis identified several networks, with four chosen for between-group analysis: salience, default mode, cognitive control, and motor networks. The default mode, cognitive control, and motor networks showed more spatial refinement over time in the exercise group compared to controls. The motor network showed increased synchrony in the exercise group with the right medial frontal gyrus compared to controls. Exercise behavior may enhance brain development in children.
doi:10.1016/j.neuroscience.2013.09.052
PMCID: PMC3995346  PMID: 24096138
Resting state fMRI; aerobic exercise; obesity; development; default mode; cognitive control
6.  Apes Communicate about Absent and Displaced Objects: Methodology Matters 
Animal cognition  2013;17(1):10.1007/s10071-013-0640-0.
Displaced reference is the ability to refer to an item that has been moved (displaced) in space and/or time, and has been called one of the true hallmarks of referential communication. Several studies suggest that nonhuman primates have this capability, but a recent experiment concluded that in a specific situation (absent entities) human infants display displaced reference but chimpanzees do not. Here we show that chimpanzees and bonobos of diverse rearing histories are capable of displaced reference to absent and displaced objects. It is likely that some of the conflicting findings from animal cognition studies are due to relatively minor methodological differences, but are compounded by interpretation errors. Comparative studies are of great importance in elucidating the evolution of human cognition, however, greater care must be taken with methodology and interpretation for these studies to accurately reflect species differences.
doi:10.1007/s10071-013-0640-0
PMCID: PMC3818454  PMID: 23681052
displacement; reference; primate; chimpanzee; bonobo; methodology
7.  Bioaccumulation Efficiency, Tissue Distribution, and Environmental Occurrence of Hepatitis E Virus in Bivalve Shellfish from France 
Applied and Environmental Microbiology  2014;80(14):4269-4276.
Hepatitis E virus (HEV), an enteric pathogen of both humans and animals, is excreted by infected individuals and is therefore present in wastewaters and coastal waters. As bivalve molluscan shellfish are known to concentrate viral particles during the process of filter feeding, they may accumulate this virus. The bioaccumulation efficiencies of oysters (Crassostrea gigas), flat oysters (Ostrea edulis), mussels (Mytilus edulis), and clams (Ruditapes philippinarum) were compared at different time points during the year. Tissue distribution analysis showed that most of the viruses were concentrated in the digestive tissues of the four species. Mussels and clams were found to be more sensitive to sporadic contamination events, as demonstrated by rapid bioaccumulation in less than 1 h compared to species of oysters. For oysters, concentrations increased during the 24-h bioaccumulation period. Additionally, to evaluate environmental occurrence of HEV in shellfish, an environmental investigation was undertaken at sites potentially impacted by pigs, wild boars, and human waste. Of the 286 samples collected, none were contaminated with hepatitis E virus, despite evidence that this virus is circulating in some French areas. It is possible that the number of hepatitis E viral particles discharged into the environment is too low to detect or that the virus may have a very short period of persistence in pig manure and human waste.
doi:10.1128/AEM.00978-14
PMCID: PMC4068666  PMID: 24795382
8.  An 8-Month Randomized Controlled Exercise Trial Alters Brain Activation During Cognitive Tasks in Overweight Children 
Obesity (Silver Spring, Md.)  2013;22(1):232-242.
Objective
Children who are less fit reportedly have lower performance on tests of cognitive control and differences in brain function. This study examined the effect of an exercise intervention on brain function during two cognitive control tasks in overweight children.
Design and Methods
Participants included 43 unfit, overweight (BMI ≥ 85th percentile) children 8- to 11-years old (91% Black), who were randomly divided into either an aerobic exercise (n = 24) or attention control group (n = 19). Each group was offered a separate instructor-led after-school program every school day for 8 months. Before and after the program, all children performed two cognitive control tasks during functional magnetic resonance imaging (fMRI): antisaccade and flanker.
Results
Compared to the control group, the exercise group decreased activation in several regions supporting antisaccade performance, including precentral gyrus and posterior parietal cortex, and increased activation in several regions supporting flanker performance, including anterior cingulate and superior frontal gyrus.
Conclusions
Exercise may differentially impact these two task conditions, or the paradigms in which cognitive control tasks were presented may be sensitive to distinct types of brain activation that show different effects of exercise. In sum, exercise appears to alter efficiency or flexible modulation of neural circuitry supporting cognitive control in overweight children.
doi:10.1002/oby.20518
PMCID: PMC4077546  PMID: 23788510
9.  Automated Cell Detection and Morphometry on Growth Plate Images of Mouse Bone 
Applied mathematics  2014;5(18):2866-2880.
Microscopy imaging of mouse growth plates is extensively used in biology to understand the effect of specific molecules on various stages of normal bone development and on bone disease. Until now, such image analysis has been conducted by manual detection. In fact, when existing automated detection techniques were applied, morphological variations across the growth plate and heterogeneity of image background color, including the faint presence of cells (chondrocytes) located deeper in tissue away from the image’s plane of focus, and lack of cell-specific features, interfered with identification of cell. We propose the first method of automated detection and morphometry applicable to images of cells in the growth plate of long bone. Through ad hoc sequential application of the Retinex method, anisotropic diffusion and thresholding, our new cell detection algorithm (CDA) addresses these challenges on bright-field microscopy images of mouse growth plates. Five parameters, chosen by the user in respect of image characteristics, regulate our CDA. Our results demonstrate effectiveness of the proposed numerical method relative to manual methods. Our CDA confirms previously established results regarding chondrocytes’ number, area, orientation, height and shape of normal growth plates. Our CDA also confirms differences previously found between the genetic mutated mouse Smad1/5CKO and its control mouse on fluorescence images. The CDA aims to aid biomedical research by increasing efficiency and consistency of data collection regarding arrangement and characteristics of chondrocytes. Our results suggest that automated extraction of data from microscopy imaging of growth plates can assist in unlocking information on normal and pathological development, key to the underlying biological mechanisms of bone growth.
doi:10.4236/am.2014.518273
PMCID: PMC4267696  PMID: 25525552
Anisotropic diffusion; cell detection; growth plate; mouse; Retinex
10.  Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis 
ACS Medicinal Chemistry Letters  2013;4(12):1238-1243.
Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo[2,3-d]pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNFα induced lethal shock.
doi:10.1021/ml400382p
PMCID: PMC4027519  PMID: 24900635
RIP1; type II kinase inhibitors; necroptosis
11.  ECOD: An Evolutionary Classification of Protein Domains 
PLoS Computational Biology  2014;10(12):e1003926.
Understanding the evolution of a protein, including both close and distant relationships, often reveals insight into its structure and function. Fast and easy access to such up-to-date information facilitates research. We have developed a hierarchical evolutionary classification of all proteins with experimentally determined spatial structures, and presented it as an interactive and updatable online database. ECOD (Evolutionary Classification of protein Domains) is distinct from other structural classifications in that it groups domains primarily by evolutionary relationships (homology), rather than topology (or “fold”). This distinction highlights cases of homology between domains of differing topology to aid in understanding of protein structure evolution. ECOD uniquely emphasizes distantly related homologs that are difficult to detect, and thus catalogs the largest number of evolutionary links among structural domain classifications. Placing distant homologs together underscores the ancestral similarities of these proteins and draws attention to the most important regions of sequence and structure, as well as conserved functional sites. ECOD also recognizes closer sequence-based relationships between protein domains. Currently, approximately 100,000 protein structures are classified in ECOD into 9,000 sequence families clustered into close to 2,000 evolutionary groups. The classification is assisted by an automated pipeline that quickly and consistently classifies weekly releases of PDB structures and allows for continual updates. This synchronization with PDB uniquely distinguishes ECOD among all protein classifications. Finally, we present several case studies of homologous proteins not recorded in other classifications, illustrating the potential of how ECOD can be used to further biological and evolutionary studies.
Author Summary
Protein structural domain databases offer a vital resource for structural bioinformatics. These databases provide functional inference for homologous structures, supply templates for structural prediction experiments, and differentiate between homologs and analogs. The rate of structure determination and deposition has increased dramatically over recent years, overwhelming the ability of current classifications to incorporate all new structures. We have developed a fast and reliable methodology for updating domain databases automatically, and created a revised hierarchy for domain classification that emphasizes evolutionary relationships. By classifying all known structures in our database with continuing automatic updates, we provide an up-to-date alternative to current resources. We illustrate several concepts that guided our classification scheme with examples of homology between domains in ECOD that are not observed in other resources.
doi:10.1371/journal.pcbi.1003926
PMCID: PMC4256011  PMID: 25474468
12.  Application of Cydia pomonella expressed sequence tags: Identification and expression of three general odorant binding proteins in codling moth 
Insect science  2012;20(5):559-574.
The codling moth, Cydia pomonella, is one of the most important pests of pome fruits in the world, yet the molecular genetics and the physiology of this insect remain poorly understood. A combined assembly of 8 341 expressed sequence tags was generated from Roche 454 GS-FLX sequencing of eight tissue-specific cDNA libraries. Putative chemosensory proteins (12) and odorant binding proteins (OBPs) (18) were annotated, which included three putative general OBP (GOBP), one more than typically reported for other Lepidoptera. To further characterize CpomGOBPs, we cloned cDNA copies of their transcripts and determined their expression patterns in various tissues. Cloning and sequencing of the 698 nt transcript for CpomGOBP1 resulted in the prediction of a 163 amino acid coding region, and subsequent RT-PCR indicated that the transcripts were mainly expressed in antennae and mouthparts. The 1 289 nt (160 amino acid) CpomGOBP2 and the novel 702 nt (169 amino acid) CpomGOBP3 transcripts are mainly expressed in antennae, mouthparts, and female abdomen tips. These results indicate that next generation sequencing is useful for the identification of novel transcripts of interest, and that codling moth expresses a transcript encoding for a new member of the GOBP subfamily.
doi:10.1111/j.1744-7917.2012.01560.x
PMCID: PMC4255946  PMID: 23956229
codling moth; EST; odorant binding proteins
13.  Discovery, design and synthesis of a selective S1P3 receptor allosteric agonist 
Potent and selective S1P3 receptor (S1P3-R) agonists may represent important proof-of-principle tools used to clarify the receptor biological function and assess the therapeutic potential of the S1P3-R in cardiovascular, inflammatory and pulmonary diseases. N,N-Dicyclohexyl-5-propylisoxazole-3-carboxamide was identified by a high-throughput screening of MLSMR library as a promising S1P3-R agonist. Rational chemical modifications of the hit allowed the identification of N,N-dicyclohexyl-5-cyclopropylisoxazole-3-carboxamide, a S1P3-R agonist endowed with submicromolar activity and exquisite selectivity over the remaining S1P1,2,4,5-R family members. A combination of ligand competition, site-directed mutagenesis and molecular modeling studies showed that the N,N-dicyclohexyl-5-cyclopropylisoxazole-3-carboxamide is an allosteric agonist and binds to the S1P3-R in a manner that does not disrupt the S1P3-R–S1P binding. The lead molecule herein disclosed constitutes a valuable pharmacological tool to explore the molecular basis of the receptor function, and provides the bases for further rational design of more potent and drug-like S1P3-R allosteric agonists.
doi:10.1016/j.bmcl.2013.09.075
PMCID: PMC3963471  PMID: 24135724
S1P3 receptor; Allosteric agonist; Cardiovascular functions
14.  Arginine Deiminase in Staphylococcus epidermidis Functions To Augment Biofilm Maturation through pH Homeostasis 
Journal of Bacteriology  2014;196(12):2277-2289.
Allelic replacement mutants were constructed within arginine deiminase (arcA1 and arcA2) to assess the function of the arginine deiminase (ADI) pathway in organic acid resistance and biofilm formation of Staphylococcus epidermidis 1457. A growth-dependent acidification assay (pH ∼5.0 to ∼5.2) determined that strain 1457 devoid of arginine deiminase activity (1457 ΔADI) was significantly less viable than the wild type following depletion of glucose and in the presence of arginine. However, no difference in viability was noted for individual 1457 ΔarcA1 (native) or ΔarcA2 (arginine catabolic mobile element [ACME]-derived) mutants, suggesting that the native and ACME-derived ADIs are compensatory in S. epidermidis. Furthermore, flow cytometry and electron paramagnetic resonance spectroscopy results suggested that organic acid stress resulted in oxidative stress that could be partially rescued by the iron chelator dipyridyl. Collectively, these results suggest that formation of hydroxyl radicals is partially responsible for cell death via organic acid stress and that ADI-derived ammonia functions to counteract this acid stress. Finally, static biofilm assays determined that viability, ammonia synthesis, and pH were reduced in strain 1457 ΔADI following 120 h of growth in comparison to strain 1457 and the arcA1 and arcA2 single mutants. It is hypothesized that ammonia synthesis via the ADI pathway is important to reduce pH stress in specific microniches that contain high concentrations of organic acids.
doi:10.1128/JB.00051-14
PMCID: PMC4054176  PMID: 24727224
15.  Genetic modulation of diabetic nephropathy among mouse strains with Ins2 Akita mutation 
Physiological Reports  2014;2(11):e12208.
Abstract
Diabetic nephropathy (DN) is a major complication of diabetes and the leading cause of end‐stage renal disease. DN is characterized by changes in kidney structure and function but the underlying genetic and molecular factors are poorly understood. We used a mouse diversity panel to explore the genetic basis of DN traits in mice carrying the Ins2 Akita mutation. Twenty‐eight Akita strains were generated by breeding this panel to DBA/2.Akita mice. Male F1 diabetic and nondiabetic littermates were evaluated for DN‐related traits. Urine albumin‐to‐creatinine ratios (ACRs), volume and cystatin C as well as blood urea nitrogen and lipoprotein levels varied significantly among the diabetic strains. For most Akita strains, ACR values increased 2‐ to 6‐fold over euglycemic control values. However, six strains exhibited changes in ACR exceeding 10‐fold with two strains (NOD/ShiLt and CBA) showing 50‐ to 83‐ fold increases. These increases are larger than previously reported among available DN mouse models establishing these strains as useful for additional studies of renal function. ACRs correlated with cystatin C (P = 0.0286), a measure of hyperfiltration and an interstitial tubular marker associated with DN onset in humans suggesting that tubule damage as well as podocyte‐stress contributed to reduced kidney function assessed by ACR. Although large changes were seen for ACRs, severe nephropathology was absent. However, glomerular hypertrophy and collagen IV content were found to vary significantly among strains suggesting a genetic basis for early onset features of DN. Our results define the range of DN phenotypes that occur among common inbred strains of mice.
Diabetic nephropathy (DN) is characterized by changes in kidney structure and function but the underlying genetic and molecular factors are poorly understood. We used a mouse diversity panel to explore the genetic basis of DN traits in mice carrying the Ins2 Akita mutation. Twenty‐eight Akita strains on different genetic backgrounds were evaluated for DN‐related traits and the results define the range of DN phenotypes that occur among common inbred strains of mice.
doi:10.14814/phy2.12208
PMCID: PMC4255814  PMID: 25428948
Akita; Animal models; Albuminuria; Diabetic nephropathy; Genetics
16.  Asymptomatic Bacteriuria Escherichia coli Are Live Biotherapeutics for UTI 
PLoS ONE  2014;9(11):e109321.
Urinary tract infections (UTI) account for approximately 8 million clinic visits annually with symptoms that include acute pelvic pain, dysuria, and irritative voiding. Empiric UTI management with antimicrobials is complicated by increasing antimicrobial resistance among uropathogens, but live biotherapeutics products (LBPs), such as asymptomatic bacteriuria (ASB) strains of E. coli, offer the potential to circumvent antimicrobial resistance. Here we evaluated ASB E. coli as LBPs, relative to ciprofloxacin, for efficacy against infection and visceral pain in a murine UTI model. Visceral pain was quantified as tactile allodynia of the pelvic region in response to mechanical stimulation with von Frey filaments. Whereas ciprofloxacin promoted clearance of uropathogenic E. coli (UPEC), it did not reduce pelvic tactile allodynia, a measure of visceral pain. In contrast, ASB E. coli administered intravesically or intravaginally provided comparable reduction of allodynia similar to intravesical lidocaine. Moreover, ASB E. coli were similarly effective against UTI allodynia induced by Proteus mirabilis, Enterococccus faecalis and Klebsiella pneumoniae. Therefore, ASB E. coli have anti-infective activity comparable to the current standard of care yet also provide superior analgesia. These studies suggest that ASB E. coli represent novel LBPs for UTI symptoms.
doi:10.1371/journal.pone.0109321
PMCID: PMC4236008  PMID: 25405579
17.  Inactivation of Patched1 induces Pdgfrα-positive Kit-negative GIST-like tumors in mice 
Gastroenterology  2012;144(1):134-144.e6.
Background and aims
A fraction of gastrointestinal stromal tumors (GIST) overexpress PDGFRA rather than KIT. Presently it is unknown if this reflects a complementary oncogenic potential of PDGFRA and KIT pathways, or heterogeneity in the cellular origin of GIST. Similarly unknown is the significance of activated Hedgehog (HH)/PATCHED1 (PTCH) signaling found in many GIST.
Methods
Mouse Ptch was conditionally inactivated using a Cre recombinase driven by the lysozyme M (LysM) promoter. Lineage tracing was done using R26R-LacZ reporter mice. Tumors were characterized by in situ hybridization, immunohistochemistry, Western blot and qRT-PCR. Cellular transformation was assessed by clonogenic assay.
Results
Inactivation of Ptch in LysM-expressing cells resulted in imatinib-responsive tumors of GIST-like localization and histology. In addition to activation of Hh signaling, the tumors showed overexpression and activation of Pdgfrα, but not of Kit. Lineage tracing revealed that LysM-expressing intestinal cells were Kit-negative. These cells were juxtapposed with Kit-positive interstitial cells of Cajal (ICC) and sometimes co-expressed Pdgfrα. In contrast to KIT, PDGFRA cooperated with HH signaling in cellular transformation.
Conclusions
Mutations in Ptch result in formation of Pdgfrα-positive Kit-negative GIST-like tumors in mice. These tumors may develop due to cooperativity between Hh and Pdgfrα pathways from Kit-negative cells in the intestine.
doi:10.1053/j.gastro.2012.09.061
PMCID: PMC4231777  PMID: 23041331
GIST; mouse model; Hedgehog and Pdgfrα signaling
18.  The role of epithelial plasticity in prostate cancer dissemination and treatment resistance 
Cancer metastasis reviews  2014;33(0):441-468.
Nearly 30,000 men die annually in the USA of prostate cancer, nearly uniformly from metastatic dissemination. Despite recent advances in hormonal, immunologic, bone-targeted, and cytotoxic chemotherapies, treatment resistance and further dissemination are inevitable in men with metastatic disease. Emerging data suggests that the phenomenon of epithelial plasticity, encompassing both reversible mesenchymal transitions and acquisition of stemness traits, may underlie this lethal biology of dissemination and treatment resistance. Understanding the molecular underpinnings of this cellular plasticity from preclinical models of prostate cancer and from biomarker studies of human metastatic prostate cancer has provided clues to novel therapeutic approaches that may delay or prevent metastatic disease and lethality over time. This review will discuss the preclinical and clinical evidence for epithelial plasticity in this rapidly changing field and relate this to clinical phenotype and resistance in prostate cancer while suggesting novel therapeutic approaches.
doi:10.1007/s10555-013-9483-z
PMCID: PMC4230790  PMID: 24414193
Epithelial plasticity; Prostate cancer; Metastasis; Epithelial–mesenchymal transition; Dissemination; Stem cell
19.  Comparative Analysis of Predicted Plastid-Targeted Proteomes of Sequenced Higher Plant Genomes 
PLoS ONE  2014;9(11):e112870.
Plastids are actively involved in numerous plant processes critical to growth, development and adaptation. They play a primary role in photosynthesis, pigment and monoterpene synthesis, gravity sensing, starch and fatty acid synthesis, as well as oil, and protein storage. We applied two complementary methods to analyze the recently published apple genome (Malus × domestica) to identify putative plastid-targeted proteins, the first using TargetP and the second using a custom workflow utilizing a set of predictive programs. Apple shares roughly 40% of its 10,492 putative plastid-targeted proteins with that of the Arabidopsis (Arabidopsis thaliana) plastid-targeted proteome as identified by the Chloroplast 2010 project and ∼57% of its entire proteome with Arabidopsis. This suggests that the plastid-targeted proteomes between apple and Arabidopsis are different, and interestingly alludes to the presence of differential targeting of homologs between the two species. Co-expression analysis of 2,224 genes encoding putative plastid-targeted apple proteins suggests that they play a role in plant developmental and intermediary metabolism. Further, an inter-specific comparison of Arabidopsis, Prunus persica (Peach), Malus × domestica (Apple), Populus trichocarpa (Black cottonwood), Fragaria vesca (Woodland Strawberry), Solanum lycopersicum (Tomato) and Vitis vinifera (Grapevine) also identified a large number of novel species-specific plastid-targeted proteins. This analysis also revealed the presence of alternatively targeted homologs across species. Two separate analyses revealed that a small subset of proteins, one representing 289 protein clusters and the other 737 unique protein sequences, are conserved between seven plastid-targeted angiosperm proteomes. Majority of the novel proteins were annotated to play roles in stress response, transport, catabolic processes, and cellular component organization. Our results suggest that the current state of knowledge regarding plastid biology, preferentially based on model systems is deficient. New plant genomes are expected to enable the identification of potentially new plastid-targeted proteins that will aid in studying novel roles of plastids.
doi:10.1371/journal.pone.0112870
PMCID: PMC4231079  PMID: 25393533
20.  Decontamination of medical devices from pathological amyloid-β-, tau- and α-synuclein aggregates 
doi:10.1186/s40478-014-0151-5
PMCID: PMC4213499  PMID: 25344093
Alzheimer’s disease; Parkinson’s disease; Dementia with Lewy bodies; Amyloid-β; Tau; α-synuclein; Prion; Aggregate; Decontamination; Medical devices
21.  The formation of source memory under distraction 
Background
It is vital to select and process relevant information while restraining irrelevant information for successful retrieval. When multiple streams of information are concurrently present, the ability to overcome distraction is very crucial for processing relevant information. Despite its significance, the neural mechanism of successful memory formation under distraction remains unclear, especially with memory for associations. The present fMRI study investigated the effect of distraction due to irrelevant stimuli in source memory.
Methods
In the MR scanner, participants studied an item and perceptual context with no distractor, a letter-distractor, or a word-distractor. Following the study phase, a source recognition test was administered in which participants were instructed to judge the study status of the test items and context of studied items. Participants’ encoding activity was back-sorted by later source recognition to find the influence of distractors in subsequent memory effects.
Results
Source memory with distractors recruited greater encoding activity in the left dorsolateral prefrontal cortex, and the bilateral inferior temporal gyrus/fusiform cortex, along with the left posterior hippocampus. However, enhanced activity in the left anterior ventrolateral prefrontal cortex and the left parahippocampal cortex predicted successful source memory regardless of the presence of a distractor.
Conclusions
These findings of subsequent memory effects suggest that strong binding of the item-context associations, as well as resistance to interference, may have greater premium in the formation of successful source memory of pictures under distraction. Further, attentional selection to the relevant target seems to play a major role in contextual binding under distraction by enhancing the viability of memory representations from interference effects of distractors.
Electronic supplementary material
The online version of this article (doi:10.1186/1744-9081-10-40) contains supplementary material, which is available to authorized users.
doi:10.1186/1744-9081-10-40
PMCID: PMC4218999  PMID: 25344289
Source memory; Distraction; fMRI; Hippocampus; Encoding
22.  Evidence for Stabilizing Selection on Codon Usage in Chromosomal Rearrangements of Drosophila pseudoobscura 
G3: Genes|Genomes|Genetics  2014;4(12):2433-2449.
There has been a renewed interest in investigating the role of stabilizing selection acting on genome-wide traits such as codon usage bias. Codon bias, when synonymous codons are used at unequal frequencies, occurs in a wide variety of taxa. Standard evolutionary models explain the maintenance of codon bias through a balance of genetic drift, mutation and weak purifying selection. The efficacy of selection is expected to be reduced in regions of suppressed recombination. Contrary to observations in Drosophila melanogaster, some recent studies have failed to detect a relationship between the recombination rate, intensity of selection acting at synonymous sites, and the magnitude of codon bias as predicted under these standard models. Here, we examined codon bias in 2798 protein coding loci on the third chromosome of D. pseudoobscura using whole-genome sequences of 47 individuals, representing five common third chromosome gene arrangements. Fine-scale recombination maps were constructed using more than 1 million segregating sites. As expected, recombination was demonstrated to be significantly suppressed between chromosome arrangements, allowing for a direct examination of the relationship between recombination, selection, and codon bias. As with other Drosophila species, we observe a strong mutational bias away from the most frequently used codons. We find the rate of synonymous and nonsynonymous polymorphism is variable between different amino acids. However, we do not observe a reduction in codon bias or the strength of selection in regions of suppressed recombination as expected. Instead, we find that the interaction between weak stabilizing selection and mutational bias likely plays a role in shaping the composition of synonymous codons across the third chromosome in D. pseudoobscura.
doi:10.1534/g3.114.014860
PMCID: PMC4267939  PMID: 25326424
codon bias; stabilizing selection; chromosomal inversions; recombination
23.  Should prostate-specific antigen be adjusted for body mass index? Data from the Baltimore Longitudinal Study of Aging 
The Journal of urology  2009;182(6):2646-2651.
Purpose
Obesity may be associated with lower prostate-specific antigen (PSA) through hemodilution. We examined the relationship between body mass index (BMI) and PSA by age in men without prostate cancer from a longitudinal aging study to determine whether PSA needs to be adjusted for BMI.
Materials and Methods
The study population included 994 men (4937 observations) without prostate cancer in the Baltimore Longitudinal Study of Aging. Mixed effects models were used to examine the relationship between PSA and BMI (kg/m2) by age. Separate models were explored in men with prostate cancer censored at diagnosis, for percent body fat measurements, for weight changes with time, and adjusting for initial prostate size in 483 men (2523 observations) with pelvic MRI measurements.
Results
In men without prostate cancer, BMI was not significantly associated with PSA after adjusting for age (p=0.06). A 10 point BMI increase was associated with a PSA difference of −0.03 ng/ml (95% CI, −0.40–0.49). Results were similar when men with prostate cancer were included, when percent body fat was substituted for BMI, and after adjusting for prostate volume. Longitudinal weight changes also had no significant association with PSA.
Conclusions
Consistent with prior studies, we found an inverse relationship between obesity and serum PSA levels. However, the magnitude of the difference was small. Thus, adjusting PSA for BMI does not appear warranted.
doi:10.1016/j.juro.2009.08.041
PMCID: PMC4197054  PMID: 19836806
PSA; prostate cancer; BMI; obesity; hemodilution
25.  Nectar Yeasts in the Tall Larkspur Delphinium barbeyi (Ranunculaceae) and Effects on Components of Pollinator Foraging Behavior 
PLoS ONE  2014;9(10):e108214.
Microorganisms frequently colonize the nectar of angiosperm species. Though capable of altering a suite of traits important for pollinator attraction, few studies exist that test the degree to which they mediate pollinator foraging behavior. The objective of our study was to fill this gap by assessing the abundance and diversity of yeasts associated with the perennial larkspur Delphinium barbeyi (Ranunculaceae) and testing whether their presence affected components of pollinator foraging behavior. Yeasts frequently colonized D. barbeyi nectar, populating 54–77% of flowers examined depending on site. Though common, the yeast community was species-poor, represented by a single species, Metschnikowia reukaufii. Female-phase flowers of D. barbeyi were more likely to have higher densities of yeasts in comparison to male-phase flowers. Pollinators were likely vectors of yeasts, as virgin (unvisited) flowers rarely contained yeasts compared to flowers open to pollinator visitation, which were frequently colonized. Finally, pollinators responded positively to the presence of yeasts. Bombus foragers both visited and probed more flowers inoculated with yeasts in comparison to uninoculated controls. Taken together, our results suggest that variation in the occurrence and density of nectar-inhabiting yeasts have the potential to alter components of pollinator foraging behavior linked to pollen transfer and plant fitness.
doi:10.1371/journal.pone.0108214
PMCID: PMC4182703  PMID: 25272164

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