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1.  The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria 
Immunity  2014;40(2):262-273.
Interleukin-22 (IL-22) is highly induced in response to infections with a variety of pathogens and its main functions are considered to be tissue repair and host defense at mucosal surfaces. Here we show that IL-22 has a previously undiscovered role during infection in that its expression suppresses the intestinal microbiota and enhances the colonization of a pathogen. IL-22 induced the expression of antimicrobial proteins, including lipocalin-2 and calprotectin, which sequester metal ions from microbes. As Salmonella Typhimurium overcomes metal starvation by lipocalin-2 and calprotectin, IL-22 boosted this pathogen’s colonization of the inflamed intestine by suppressing commensal Enterobacteriaceae, which in the absence of IL-22 overgrew S. Typhimurium. Thus, IL-22 expression can tip the balance between pathogenic and commensal bacteria in favor of a pathogen. Taken together, IL-22 induction can be exploited by pathogens to suppress the growth of their closest competitors, thereby enhancing pathogen colonization of mucosal surfaces.
PMCID: PMC3964146  PMID: 24508234
2.  RASTtk: A modular and extensible implementation of the RAST algorithm for building custom annotation pipelines and annotating batches of genomes 
Scientific Reports  2015;5:8365.
The RAST (Rapid Annotation using Subsystem Technology) annotation engine was built in 2008 to annotate bacterial and archaeal genomes. It works by offering a standard software pipeline for identifying genomic features (i.e., protein-encoding genes and RNA) and annotating their functions. Recently, in order to make RAST a more useful research tool and to keep pace with advancements in bioinformatics, it has become desirable to build a version of RAST that is both customizable and extensible. In this paper, we describe the RAST tool kit (RASTtk), a modular version of RAST that enables researchers to build custom annotation pipelines. RASTtk offers a choice of software for identifying and annotating genomic features as well as the ability to add custom features to an annotation job. RASTtk also accommodates the batch submission of genomes and the ability to customize annotation protocols for batch submissions. This is the first major software restructuring of RAST since its inception.
PMCID: PMC4322359  PMID: 25666585
3.  A highly abundant bacteriophage discovered in the unknown sequences of human faecal metagenomes 
Nature communications  2014;5:4498.
Metagenomics, or sequencing of the genetic material from a complete microbial community, is a promising tool to discover novel microbes and viruses. Viral metagenomes typically contain many unknown sequences. Here we describe the discovery of a previously unidentified bacteriophage present in the majority of published human fecal metagenomes, which we refer to as crAssphage. Its ~97 kbp genome is six times more abundant in publicly available metagenomes than all other known phages together; comprises up to 90% and 22% of all reads in virus-like particle (VLP)-derived metagenomes and total community metagenomes, respectively; and totals 1.68% of all human fecal metagenomic sequencing reads in the public databases. The majority of crAssphage-encoded proteins match no known sequences in the database, which is why it was not detected before. Using a new co-occurrence profiling approach, we predict a Bacteroides host for this phage, consistent with Bacteroides-related protein homologs and a unique carbohydrate-binding domain encoded in the phage genome,.
PMCID: PMC4111155  PMID: 25058116
Human virome; biological dark matter; metagenome assembly; phage-host prediction; depth profiles
4.  Cell-type-specific level of DNA nucleotide excision repair in primary human mammary and ovarian epithelial cell cultures 
Cell and tissue research  2008;333(3):461-467.
DNA repair, a fundamental function of cellular metabolism, has long been presumed to be constitutive and equivalent in all cells. However, we have previously shown that normal levels of nucleotide excision repair (NER) can vary by 20-fold in a tissue-specific pattern. We have now successfully established primary cultures of normal ovarian tissue from seven women by using a novel culture system originally developed for breast epithelial cells. Epithelial cells in these cultures aggregated to form three-dimensional structures called “attached ovarian epispheres”. The availability of these actively proliferating cell cultures allowed us to measure NER functionally and quantitatively by the unscheduled DNA synthesis (UDS) assay, a clinical test used to diagnose constitutive deficiencies in NER capacity. We determined that ovarian epithelial cells manifested an intermediate level of NER capacity in humans, viz., only 25% of that of foreskin fibroblasts, but still 2.5-fold higher than that of peripheral blood lymphocytes. This level of DNA repair capacity was indistinguishable from that of normal breast epithelial cells, suggesting that it might be characteristic of the epithelial cell type. Similar levels of NER activity were observed in cultures established from a disease-free known carrier of a BRCA1 truncation mutation, consistent with previous normal results shown in breast epithelium and blood lymphocytes. These results establish that at least three “normal” levels of such DNA repair occur in human tissues, and that NER capacity is epigenetically regulated during cell differentiation and development.
PMCID: PMC4301738  PMID: 18575893
Primary ovarian epithelial culture; Nucleotide excision repair; Unscheduled DNA synthesis; Xeroderma pigmentosum; BRCA1; Human
5.  Dissociable Neural Mechanisms Underlying the Modulation of Pain and Anxiety? An fMRI Pilot Study 
PLoS ONE  2014;9(12):e110654.
The down-regulation of pain through beliefs is commonly discussed as a form of emotion regulation. In line with this interpretation, the analgesic effect has been shown to co-occur with reduced anxiety and increased activity in the ventrolateral prefrontal cortex (VLPFC), which is a key region of emotion regulation. This link between pain and anxiety modulation raises the question whether the two effects are rooted in the same neural mechanism. In this pilot fMRI study, we compared the neural basis of the analgesic and anxiolytic effect of two types of threat modulation: a “behavioral control” paradigm, which involves the ability to terminate a noxious stimulus, and a “safety signaling” paradigm, which involves visual cues that signal the threat (or absence of threat) that a subsequent noxious stimulus might be of unusually high intensity. Analgesia was paralleled by VLPFC activity during behavioral control. Safety signaling engaged elements of the descending pain control system, including the rostral anterior cingulate cortex that showed increased functional connectivity with the periaqueductal gray and VLPFC. Anxiety reduction, in contrast, scaled with dorsolateral prefrontal cortex activation during behavioral control but had no distinct neural signature during safety signaling. Our pilot data therefore suggest that analgesic and anxiolytic effects are instantiated in distinguishable neural mechanisms and differ between distinct stress- and pain-modulatory approaches, supporting the recent notion of multiple pathways subserving top-down modulation of the pain experience. Additional studies in larger cohorts are needed to follow up on these preliminary findings.
PMCID: PMC4266493  PMID: 25502237
Ulcerative colitis (UC) and Crohn’s disease (CD) are two forms of chronic inflammatory bowel disease. CD4 T cells play a central role in the pathogenesis of both diseases. Smoking affects both UC and CD but with opposite effects, ameliorating UC and worsening CD. We hypothesized that the severity of gut inflammation could be modulated through T-cell nicotinic acetylcholine receptors (nAChRs) and that the exact clinical outcome would depend on the repertoire of nAChRs on CD4 T cells mediating each form of colitis. We measured clinical and immunologic outcomes of treating BALB/c mice with oxazolone- and TNBS-induced colitides by nicotine. Nicotine attenuated oxazolone colitis, which was associated with increased percentage of colonic Tregs and a reduction of Th17 cells. TCR stimulation of naïve CD4+CD62L+ T cells in the presence of nicotine upregulated expression of Foxp3. In marked contrast, nicotine worsened TNBS colitis, and this was associated with increased Th17 cells among colonic CD4 T cells. Nicotine upregulated IL-10 and inhibited IL-17 production, which could be abolished by exogenous IL-12 that also abolished the nicotine-dependent upregulation of Tregs. The dichotomous action of nicotine resulted from the up- and downregulation of anti-inflammatory α7 nAChR on colonic CD4 T cells induced by cytokines characteristic of the inflammatory milieu in oxazolone (IL-4), and TNBS (IL-12) colitis, respectively. These findings help explain the dichotomous effect of smoking in patients with UC and CD, and underscore the potential for nicotinergic drugs in regulating colonic inflammation.
PMCID: PMC4260719  PMID: 21784975
oxazolone colitis; TNBS colitis; Tregs; Th17 cells; α7 nicotinic receptor; IL-4; IL-12
7.  Self-Assembly of VPS41 Promotes Sorting Required for Biogenesis of the Regulated Secretory Pathway 
Developmental cell  2013;27(4):425-437.
The regulated release of polypeptides has a central role in physiology, behavior, and development, but the mechanisms responsible for production of the large dense core vesicles (LDCVs) capable of regulated release have remained poorly understood. Recent work has implicated cytosolic adaptor protein AP-3 in the recruitment of LDCV membrane proteins that confer regulated release. However, AP-3 in mammals has been considered to function in the endolysosomal pathway and in the biosynthetic pathway only in yeast. We now find that the mammalian homolog of yeast VPS41, a member of the homotypic fusion and vacuole protein sorting (HOPS) complex that delivers biosynthetic cargo to the endocytic pathway in yeast, promotes LDCV formation through a common mechanism with AP-3, indicating a conserved role for these proteins in the biosynthetic pathway. VPS41 also self-assembles into a lattice, suggesting that it acts as a coat protein for AP-3 in formation of the regulated secretory pathway.
PMCID: PMC3974617  PMID: 24210660
8.  A population of glomerular glutamatergic neurons controls sensory information transfer in the mouse olfactory bulb 
Nature communications  2014;5:3791.
In sensory systems, peripheral organs convey sensory inputs to relay networks where information is shaped by local microcircuits before being transmitted to cortical areas. In the olfactory system, odorants evoke specific patterns of sensory neuron activity which are transmitted to output neurons in olfactory bulb glomeruli. How sensory information is transferred and shaped at this level remains still unclear. Here we employ mouse genetics, 2-photon microscopy, electrophysiology and optogenetics, to identify a novel population of glutamatergic neurons (VGLUT3+) in the glomerular layer of the adult mouse olfactory bulb as well as several of their synaptic targets. Both peripheral and serotoninergic inputs control VGLUT3+ neurons firing. Furthermore, we show that VGLUT3+ neurons photostimulation in vivo strongly suppresses both spontaneous and odor-evoked firing of bulbar output neurons. In conclusion, we identify and characterize here a microcircuit controlling the transfer of sensory information at an early stage of the olfactory pathway.
PMCID: PMC4028618  PMID: 24804702
vesicular glutamate transporter; olfaction; external tufted cells; serotonin; channelrhodopsin
9.  Efficient, Complete Deletion of Synaptic Proteins using CRISPR 
Neuron  2014;83(5):1051-1057.
One of the most powerful ways to test the function of a protein is to characterize the consequences of its deletion. In the past, this has involved inactivation of the gene by homologous recombination either in the germline or later through conditional deletion. RNA interference (RNAi) provides an alternative way to knock down proteins, but both of these approaches have their limitations. Recently, the CRISPR/Cas9 system has suggested another way to selectively inactivate genes. We have now tested this system in postmitotic neurons by targeting two well-characterized synaptic proteins, the obligatory GluN1 subunit of the NMDA receptor and the GluA2 subunit of the AMPA receptor. Expression of CRISPR/Cas9 in hippocampal slice cultures completely eliminated NMDA receptor and GluA2 function. CRISPR/Cas9 thus provides a powerful tool to study the function of synaptic proteins.
PMCID: PMC4195490  PMID: 25155957
10.  Biomarker-based ovarian carcinoma typing: a histological investigation in the Ovarian Tumor Tissue Analysis consortium 
Ovarian carcinoma is composed of five major histological types which associate with outcome and predict therapeutic response. Our aim was to evaluate histological type assessments across centres participating in the Ovarian Tumor Tissue Analysis (OTTA) consortium using an immunohistochemical (IHC) prediction model.
Tissue microarrays (TMAs) and clinical data were available for 524 pathologically confirmed ovarian carcinomas. Centralized IHC was performed for ARID1A, CDKN2A, DKK1, HNF1B, MDM2, PGR, TP53, TFF3, VIM, and WT1, and three histological type assessments were compared: the original pathologic type, an IHC-based calculated type (termed TB_COSPv2), and a WT1-assisted TMA core review.
The concordance between TB_COSPv2 type and original type was 73%. Applying WT1-assisted core review, the remaining 27% discordant cases subdivided into unclassifiable (6%), TB_COSPv2 error (6%), and original type error (15%). The largest discordant subgroup was classified as endometrioid carcinoma (EC) by original type and as high-grade serous carcinoma (HGSC) by TB_COSPv2. When TB_COSPv2 classification was used, the difference in overall survival of EC compared to HGSC became significant (RR 0.60, 95% CI 0.37–0.93, p=0.021), consistent with previous reports. In addition, 71 cases with unclear original type could be histologically classified by TB_COSPv2.
Research cohorts, particularly those across different centres within consortia, show significant variability in original histological type diagnosis. Our IHC-based reclassification produced more homogeneous types with respect to outcome than original type.
Biomarker-based classification of ovarian carcinomas is feasible, improves comparability of results across research studies, and can reclassify cases which lack reliable original pathology.
PMCID: PMC3955399  PMID: 23880734
ovarian cancer; type; biomarker; immunohistochemistry; typing
11.  The Function of α-Synuclein 
Neuron  2013;79(6):10.1016/j.neuron.2013.09.004.
Human genetics has indicated a causal role for the protein α-synuclein in the pathogenesis of familial Parkinson’s disease (PD), and the aggregation of synuclein in essentially all patients with PD suggests a central role for this protein in the sporadic disorder. Indeed, the accumulation of misfolded α-synuclein now defines multiple forms of neural degeneration. Like many of the proteins that accumulate in other neurodegenerative disorders, however, the normal function of synuclein remains poorly understood. α-Synuclein localizes specifically to the nerve terminal and inhibits neurotransmitter release when over-expressed, but the knockout has a modest effect on synaptic transmission, suggesting alternative presynaptic roles. Natively unstructured, synuclein adopts a helical conformation on membrane binding and recent work suggests a role in membrane remodeling. In neural degeneration, synuclein misfolds and aggregates as a β-sheet. Multiple observations now suggest propagation of the misfolded protein as a prion, providing a mechanism for the spread of degeneration through the neuraxis. However, the factors that trigger the original misfolding remain unknown.
PMCID: PMC3866954  PMID: 24050397
12.  Well-Loved Music Robustly Relieves Pain: A Randomized, Controlled Trial 
PLoS ONE  2014;9(9):e107390.
Music has pain-relieving effects, but its mechanisms remain unclear. We sought to verify previously studied analgesic components and further elucidate the underpinnings of music analgesia. Using a well-characterized conditioning-enhanced placebo model, we examined whether boosting expectations would enhance or interfere with analgesia from strongly preferred music. A two-session experiment was performed with 48 healthy, pain experiment-naïve participants. In a first cohort, 36 were randomized into 3 treatment groups, including music enhanced with positive expectancy, non-musical sound enhanced with positive expectancy, and no expectancy enhancement. A separate replication cohort of 12 participants received only expectancy-enhanced music following the main experiment to verify the results of expectancy-manipulation on music. Primary outcome measures included the change in subjective pain ratings to calibrated experimental noxious heat stimuli, as well as changes in treatment expectations. Without conditioning, expectations were strongly in favor of music compared to non-musical sound. While measured expectations were enhanced by conditioning, this failed to affect either music or sound analgesia significantly. Strongly preferred music on its own was as pain relieving as conditioning-enhanced strongly preferred music, and more analgesic than enhanced sound. Our results demonstrate the pain-relieving power of personal music even over enhanced expectations.
Trial Information NCT01835275.
PMCID: PMC4161415  PMID: 25211164
13.  Laminar and columnar development of barrel cortex relies on thalamocortical neurotransmission 
Neuron  2013;79(5):970-986.
A dynamic interplay between intrinsic regional molecular cues and extrinsic factors from the thalamus shape multiple features of early cortical development. It remains uncertain and controversial, however, whether the initial formation of cortical columns depends on neuronal activity, and there is little evidence that cortical lamination or neuronal differentiation is influenced by extrinsic activity. We examined the role of thalamic-derived factors in cortical development by selectively eliminating glutamatergic synaptic transmission from thalamocortical neurons in mice, and found that eliminating thalamocortical neurotransmission prevented the formation of ‘barrel’ columns in somatosensory cortex. Interestingly, based on cytoarchitectonic criteria and genetic markers, blocking thalamocortical neurotransmission also perturbed the development of superficial cortical lamina and the morphological development of neurons. These experiments demonstrate that barrels and aspects of the layer-dependent pattern of cortical cytoarchitecture, gene expression and neuronal differentiation depend on thalamocortical neurotransmission, extending the apparent influence of extrinsic, presumably activity-dependent factors, on cortical development.
PMCID: PMC3768017  PMID: 24012009
14.  Genetic targeting and physiological features of VGLUT3+ amacrine cells 
Visual neuroscience  2011;28(5):381-392.
Amacrine cells constitute a diverse class of interneurons that contribute to visual signal processing in the inner retina, but surprisingly, little is known about the physiology of most amacrine cell subtypes. Here, we have taken advantage of the sparse expression of vesicular glutamate transporter 3 (VGLUT3) in the mammalian retina to target the expression of yellow fluorescent protein (YFP) to a unique population of amacrine cells using a new transgenic mouse line. Electrophysiological recordings made from YFP-positive (VGLUT3+) amacrine cells provide the first functional data regarding the active membrane properties and synaptic connections of this recently identified cell type. We found that VGLUT3+ amacrine cells receive direct synaptic input from bipolar cells via both N-methyl-d-aspartate receptors (NMDARs) and non-NMDARs. Voltage-gated sodium channels amplified these excitatory inputs but repetitive spiking was never observed. VGLUT3+ amacrine cells responded transiently to both light increments (ON response) and decrements (OFF response); ON responses consisted exclusively of inhibitory inputs, while OFF responses comprised both excitatory and inhibitory components, although the inhibitory conductance was larger in amplitude and longer in time course. The physiological properties and anatomical features of the VGLUT3+ amacrine cells suggest that this bistratified interneuron may play a role in disinhibitory signaling and/or crossover inhibition between parallel pathways in the retina.
PMCID: PMC4150031  PMID: 21864449
Interneurons; Transgenic Cre mice; Synaptic physiology
15.  Sequencing at sea: challenges and experiences in Ion Torrent PGM sequencing during the 2013 Southern Line Islands Research Expedition 
PeerJ  2014;2:e520.
Genomics and metagenomics have revolutionized our understanding of marine microbial ecology and the importance of microbes in global geochemical cycles. However, the process of DNA sequencing has always been an abstract extension of the research expedition, completed once the samples were returned to the laboratory. During the 2013 Southern Line Islands Research Expedition, we started the first effort to bring next generation sequencing to some of the most remote locations on our planet. We successfully sequenced twenty six marine microbial genomes, and two marine microbial metagenomes using the Ion Torrent PGM platform on the Merchant Yacht Hanse Explorer. Onboard sequence assembly, annotation, and analysis enabled us to investigate the role of the microbes in the coral reef ecology of these islands and atolls. This analysis identified phosphonate as an important phosphorous source for microbes growing in the Line Islands and reinforced the importance of L-serine in marine microbial ecosystems. Sequencing in the field allowed us to propose hypotheses and conduct experiments and further sampling based on the sequences generated. By eliminating the delay between sampling and sequencing, we enhanced the productivity of the research expedition. By overcoming the hurdles associated with sequencing on a boat in the middle of the Pacific Ocean we proved the flexibility of the sequencing, annotation, and analysis pipelines.
PMCID: PMC4145072  PMID: 25177534
Genomics; Sequencing; Expeditions; Metagenomics; Environmental microbiology; Coral reef; Vibrio
16.  Comparative genomics of 274 Vibrio cholerae genomes reveals mobile functions structuring three niche dimensions 
BMC Genomics  2014;15(1):654.
Vibrio cholerae is a globally dispersed pathogen that has evolved with humans for centuries, but also includes non-pathogenic environmental strains. Here, we identify the genomic variability underlying this remarkable persistence across the three major niche dimensions space, time, and habitat.
Taking an innovative approach of genome-wide association applicable to microbial genomes (GWAS-M), we classify 274 complete V. cholerae genomes by niche, including 39 newly sequenced for this study with the Ion Torrent DNA-sequencing platform. Niche metadata were collected for each strain and analyzed together with comprehensive annotations of genetic and genomic attributes, including point mutations (single-nucleotide polymorphisms, SNPs), protein families, functions and prophages.
Our analysis revealed that genomic variations, in particular mobile functions including phages, prophages, transposable elements, and plasmids underlie the metadata structuring in each of the three niche dimensions. This underscores the role of phages and mobile elements as the most rapidly evolving elements in bacterial genomes, creating local endemicity (space), leading to temporal divergence (time), and allowing the invasion of new habitats. Together, we take a data-driven approach for comparative functional genomics that exploits high-volume genome sequencing and annotation, in conjunction with novel statistical and machine learning analyses to identify connections between genotype and phenotype on a genome-wide scale.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-654) contains supplementary material, which is available to authorized users.
PMCID: PMC4141962  PMID: 25096633
Functional genomics; Mobile elements; Phages; Niche adaptation; Vibrio; Genome evolution; Genotype-phenotype association; Random forest
17.  Effects of L-Theanine on Posttraumatic Stress Disorder Induced Changes in Rat Brain Gene Expression 
The Scientific World Journal  2014;2014:419032.
Posttraumatic stress disorder (PTSD) is characterized by the occurrence of a traumatic event that is beyond the normal range of human experience. The future of PTSD treatment may specifically target the molecular mechanisms of PTSD. In the US, approximately 20% of adults report taking herbal products to treat medical illnesses. L-theanine is the amino acid in green tea primarily responsible for relaxation effects. No studies have evaluated the potential therapeutic properties of herbal medications on gene expression in PTSD. We evaluated gene expression in PTSD-induced changes in the amygdala and hippocampus of Sprague-Dawley rats. The rats were assigned to PTSD-stressed and nonstressed groups that received either saline, midazolam, L-theanine, or L-theanine + midazolam. Amygdala and hippocampus tissue samples were analyzed for changes in gene expression. One-way ANOVA was used to detect significant difference between groups in the amygdala and hippocampus. Of 88 genes examined, 17 had a large effect size greater than 0.138. Of these, 3 genes in the hippocampus and 5 genes in the amygdala were considered significant (P < 0.05) between the groups. RT-PCR analysis revealed significant changes between groups in several genes implicated in a variety of disorders ranging from PTSD, anxiety, mood disorders, and substance dependence.
PMCID: PMC4137547  PMID: 25165739
18.  IL-18-primed helper NK cells collaborate with dendritic cells to promote recruitment of effector CD8+ T cells to the tumor microenvironment 
Cancer research  2013;73(15):4653-4662.
Chemokine-driven interactions of immune cells are essential for effective anti-tumor immunity. Human natural killer (NK) cells can be primed by the IL1-related pro-inflammatory cytokine IL-18 for unique helper activity, which promotes dendritic cell (DC) activation and DC-mediated induction of type-1 immune responses against cancer. Here we show that such IL-18-primed ‘helper’ NK cells produce high levels of the immature DC (iDC)-attracting chemokines CCL3 and CCL4 upon exposure to tumor cells or the additional inflammatory signals IFNα, IL-15, IL-12, or IL-2. These ‘helper’ NK cells potently attract iDCs in a CCR5-dependent mechanism and induce high DC production of CXCR3 and CCR5 ligands (CXCL9, CXCL10, and CCL5), facilitating the subsequent recruitment of type-1 effector CD8+ T (Teff) cells. Using cells isolated from the malignant ascites of patients with advanced ovarian cancer, we show that ‘helper’ NK cell-inducing factors can be used to enhance local production of Teff cell-recruiting chemokines. Our findings reveal the unique chemokine expression profile of ‘helper’ NK cells and highlight the potential for utilizing two-signal-activated NK cells to promote homing of type-1 immune effectors to the human tumor environment.
PMCID: PMC3780558  PMID: 23761327
natural killer cells; dendritic cells; chemokines; IL-18; ovarian cancer
19.  Sustained deep-tissue pain alters functional brain connectivity 
Pain  2013;154(8):1343-1351.
Recent functional brain connectivity studies have contributed to our understanding of the neurocircuitry supporting pain perception. However, evoked-pain connectivity studies have employed cutaneous and/or brief stimuli, which induce sensations that differ appreciably from the clinical pain experience. Sustained myofascial pain evoked by pressure cuff affords an excellent opportunity to evaluate functional connectivity change to more clinically-relevant sustained deep-tissue pain. Connectivity in specific networks known to be modulated by evoked pain (sensorimotor, salience, dorsal attention, fronto-parietal control and default mode networks; SMN, SLN, DAN, FCN and DMN) was evaluated with functional-connectivity MRI, both at rest and during a sustained (6-minute) pain state in healthy adults. We found that pain was stable with no significant changes of subjects’ pain ratings over the stimulation period. Sustained pain reduced connectivity between the SMN and the contralateral leg primary sensorimotor (S1/M1) representation. Such SMN-S1/M1 connectivity decreases were also accompanied by and correlated with increased SLN-S1/M1 connectivity, suggesting recruitment of activated S1/M1 from SMN to SLN. Sustained pain also increased DAN connectivity to pain processing regions such as mid-cingulate cortex, posterior insula and putamen. Moreover, greater connectivity during pain between contralateral S1/M1 and posterior insula, thalamus, putamen, and amygdala, was associated with lower cuff pressures needed to reach the targeted pain sensation. These results demonstrate that sustained pain disrupts resting S1/M1 connectivity by shifting it to a network known to process stimulus salience. Furthermore, increased connectivity between S1/M1 and both sensory and affective processing areas may be an important contribution to inter-individual differences in pain sensitivity.
PMCID: PMC3700646  PMID: 23718988
somatosensory; sensorimotor network; salience network; dorsal attention network; fronto-parietal control network; and functional connectivity
20.  MUC1 Positive, Kras and Pten Driven Mouse Gynecologic Tumors Replicate Human Tumors and Vary in Survival and Nuclear Grade Based on Anatomical Location 
PLoS ONE  2014;9(7):e102409.
Activating mutations of Kras oncogene and deletions of Pten tumor suppressor gene play important roles in cancers of the female genital tract. We developed here new preclinical models for gynecologic cancers, using conditional (Cre-loxP) mice with floxed genetic alterations in Kras and Pten. The triple transgenic mice, briefly called MUC1KrasPten, express human MUC1 antigen as self and carry a silent oncogenic KrasG12D and Pten deletion mutation. Injection of Cre-encoding adenovirus (AdCre) in the ovarian bursa, oviduct or uterus activates the floxed mutations and initiates ovarian, oviductal, and endometrial cancer, respectively. Anatomical site-specific Cre-loxP recombination throughout the genital tract of MUC1KrasPten mice leads to MUC1 positive genital tract tumors, and the development of these tumors is influenced by the anatomical environment. Endometrioid histology was consistently displayed in all tumors of the murine genital tract (ovaries, oviducts, and uterus). Tumors showed increased expression of MUC1 glycoprotein and triggered de novo antibodies in tumor bearing hosts, mimicking the immunobiology seen in patients. In contrast to the ovarian and endometrial tumors, oviductal tumors showed higher nuclear grade. Survival for oviduct tumors was significantly lower than for endometrial tumors (p = 0.0015), yet similar to survival for ovarian cancer. Oviducts seem to favor the development of high grade tumors, providing preclinical evidence in support of the postulated role of fallopian tubes as the originating site for high grade human ovarian tumors.
PMCID: PMC4117479  PMID: 25078979
21.  Individual Variation in Sleep Quality and Duration Is Related to Cerebral Mu Opioid Receptor Binding Potential during Tonic Laboratory Pain in Healthy Subjects 
Pain medicine (Malden, Mass.)  2013;14(12):1882-1892.
Although poor sleep is a consequence of pain, sleep disturbance reciprocally induces hyperalgesia and exacerbates clinical pain. Conceptual models of chronic pain implicate dysfunctional supraspinal pain processing mechanisms, mediated in part by endogenous opioid peptides. Our preliminary work indicates that sleep disruption impairs psychophysical measures of descending pain modulation, but few studies have investigated whether insufficient sleep may be associated with alterations in endogenous opioid systems. This preliminary, exploratory investigation sought to examine the relationship between sleep and functioning of the cerebral mu opioid system during the experience of pain in healthy participants.
Subjects and Design
Twelve healthy volunteers participated in a 90-minute positron emission tomography imaging scan using [11C]Carfentanil, a mu opioid receptors agonist. During the session, pain responses to a 10% topical capsaicin cream were continuously rated on a 0–100 scale. Participants also completed the Pittsburgh Sleep Quality Index (PSQI).
Poor sleep quality (PSQI) was positively and significantly associated with greater binding potential (BP) in regions within the frontal lobes. In addition, sleep duration was negatively associated with BP in these areas as well as the temporal lobe and anterior cingulate.
These findings suggest that poor sleep quality and short sleep duration are associated with endogenous opioid activity in these brain regions during the application of a noxious stimulus. Elucidating the role of the endogenous opioid system in mediating some of the associations between sleep and pain could significantly improve our understanding of the pathophysiology of chronic pain and might advance clinical practice by suggesting interventions that could buffer the adverse effects of poor sleep on pain.
PMCID: PMC4104524  PMID: 24102962
Sleep; Pain; Capsaicin; PET; Imaging; Binding Potential; [11 C]Carfentanil
22.  Probiotic Bacteria Reduce Salmonella Typhimurium Intestinal Colonization by Competing for Iron 
Cell host & microbe  2013;14(1):26-37.
Host inflammation alters the availability of nutrients such as iron to limit microbial growth. However, Salmonella enterica serovar Typhimurium thrives in the inflamed gut by scavenging for iron with siderophores. By administering Escherichia coli strain Nissle 1917, which assimilates iron by similar mechanisms, we show that this non-pathogenic bacterium can outcompete and reduce S. Typhimurium colonization in mouse models of acute colitis and chronic persistent infection. This probiotic activity depends on E. coli Nissle iron acquisition as mutants deficient in iron uptake colonize the intestine but do not reduce S. Typhimurium colonization. Additionally, the ability of E. coli Nissle to overcome iron restriction by the host protein lipocalin-2, which counteracts some siderophores, is essential as S. Typhimurium is unaffected by E. coli Nissle in lipocalin-2-deficient mice. Thus, iron availability impacts S. Typhimurium growth and E. coli Nissle reduces S. Typhimurium intestinal colonization by competing for this limiting nutrient.
PMCID: PMC3752295  PMID: 23870311
23.  Integrating Pain Management in Clinical Practice 
There is much evidence to suggest that psychological and social issues are predictive of pain severity, emotional distress, work disability, and response to medical treatments among persons with chronic pain. Psychologists can play an important role in the identification of psychological and social dysfunction and in matching personal characteristics to effective interventions as part of a multidisciplinary approach to pain management, leading to a greater likelihood of treatment success. The assessment of different domains using semi-structured clinical interviews and standardized self-report measures permits identification of somatosensory, emotional, cognitive, behavioral and social issues in order to facilitate treatment planning. We briefly describe measures to assess constructs related to pain and intervention strategies for the behavioral treatment of chronic pain and discuss related psychiatric and substance abuse issues. Finally, we offer a future look at the role of integrating pain management in clinical practice in the psychological assessment and treatment for persons with chronic pain.
PMCID: PMC4099944  PMID: 22383018
Chronic pain; assessment; coping; behavioral; psychological interventions; substance abuse
24.  Neurotransmitter Co-release: Mechanism and Physiological Role 
Annual review of physiology  2011;74:225-243.
Neurotransmitter identity is a defining feature of all neurons because it constrains the type of information they convey, but it has become clear that many neurons in fact release multiple transmitters. Although the physiological role for co-release has remained poorly understood, the vesicular uptake of one transmitter can regulate filling with the other by influencing expression of the H+ electrochemical driving force. In addition, the sorting of vesicular neurotransmitter transporters and other synaptic vesicle proteins into different vesicle pools suggests the potential for distinct modes of release. Co-release thus serves multiple roles in synaptic transmission.
PMCID: PMC4090038  PMID: 22054239
neurotransmitter co-release; neurotransmitter co-storage; synaptic vesicle pools; vesicular neurotransmitter transporters
25.  Re-Thinking the Fear Avoidance Model: Toward a Multi-Dimensional Framework of Pain-Related Disability 
Pain  2013;154(11):2262-2265.
PMCID: PMC4078976  PMID: 23748115
Fear avoidance model; pain; disability; psychological risk factors

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