Recent Stanford Publications in PubMed
- Tropical Forest Fragmentation Affects Floral Visitors but Not the Structure of Individual-Based Palm-Pollinator Networks.Dáttilo W, Aguirre A, Quesada M, Dirzo RPLoS One
- Crystal Structure of a Two-Subunit TrkA Octameric Gating Ring Assembly.Deller MC, Johnson HA, Miller MD, Spraggon G, Elsliger MA, Wilson IA, Lesley SAPLoS One
- Fungi in Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis.Moss RBSemin Respir Crit Care Med
- Stress inoculation modeled in mice.Brockhurst J, Cheleuitte-Nieves C, Buckmaster CL, Schatzberg AF, Lyons DMTransl Psychiatry
- Definitions of Cardiovascular Insufficiency and Relation to Outcomes in Critically Ill Newborn Infants.Fernandez E, Watterberg KL, Faix RG, Yoder BA, Walsh MC, Lacy CB, Osborne KA, Das A, Kendrick DE, Stoll BJ, Poindexter BB, Laptook AR, Kennedy KA, Schibler K, Bell EF, Van Meurs KP, Frantz ID, Goldberg RN, Shankaran S, Carlo WA, Ehrenkranz RA, Sánchez PJ, Higgins RD, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research NetworkAm J Perinatol
- Integrative, dynamic structural biology at atomic resolution-it's about time.van den Bedem H, Fraser JSNat Methods
- Structure-based discovery of NANOG variant with enhanced properties to promote self-renewal and reprogramming of pluripotent stem cells.Hayashi Y, Caboni L, Das D, Yumoto F, Clayton T, Deller MC, Nguyen P, Farr CL, Chiu HJ, Miller MD, Elsliger MA, Deacon AM, Godzik A, Lesley SA, Tomoda K, Conklin BR, Wilson IA, Yamanaka S, Fletterick RJProc Natl Acad Sci U S A
- CD14-expressing cancer cells establish the inflammatory and proliferative tumor microenvironment in bladder cancer.Cheah MT, Chen JY, Sahoo D, Contreras-Trujillo H, Volkmer AK, Scheeren FA, Volkmer JP, Weissman ILProc Natl Acad Sci U S A
- Structural basis for the geometry-driven localization of a small protein.Gill RL, Castaing JP, Hsin J, Tan IS, Wang X, Huang KC, Tian F, Ramamurthi KSProc Natl Acad Sci U S A
- Environmental tipping points significantly affect the cost-benefit assessment of climate policies.Cai Y, Judd KL, Lenton TM, Lontzek TS, Narita DProc Natl Acad Sci U S A
- Lipoprotein particles and size, total and high molecular weight adiponectin, and leptin in relation to incident coronary heart disease among severely obese postmenopausal women: The Women's Health Initiative Observational Study.Mackey RH, McTigue KM, Chang YF, Barinas-Mitchell E, Evans RW, Tinker LF, Lewis CE, Manson JE, Stefanick ML, Howard BV, Phillips LS, Liu S, Kulick D, Kuller LHBBA Clin
- Theranostic mesoporous silica nanoparticles biodegrade after pro-survival drug delivery and ultrasound/magnetic resonance imaging of stem cells.Kempen PJ, Greasley S, Parker KA, Campbell JL, Chang HY, Jones JR, Sinclair R, Gambhir SS, Jokerst JVTheranostics
- Organoid modeling for cancer precision medicine.Cantrell MA, Kuo CJGenome Med
- Evidence-based guideline summary: Evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine.Kang PB, Morrison L, Iannaccone ST, Graham RJ, Bönnemann CG, Rutkowski A, Hornyak J, Wang CH, North K, Oskoui M, Getchius TS, Cox JA, Hagen EE, Gronseth G, Griggs RCNeurology
- Ability To Develop Broadly Neutralizing HIV-1 Antibodies Is Not Restricted by the Germline Ig Gene Repertoire.Scheepers C, Shrestha RK, Lambson BE, Jackson KJ, Wright IA, Naicker D, Goosen M, Berrie L, Ismail A, Garrett N, Abdool Karim Q, Abdool Karim SS, Moore PL, Travers SA, Morris LJ Immunol
- Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.Xia M, Viera-Hutchins L, Garcia-Lloret M, Noval Rivas M, Wise P, McGhee SA, Chatila ZK, Daher N, Sioutas C, Chatila TAJ Allergy Clin Immunol
- Noninvasive pulmonary nodule elastometry by CT and deformable image registration.Negahdar M, Fasola CE, Yu AS, von Eyben R, Yamamoto T, Diehn M, Fleischmann D, Tian L, Loo BW, Maxim PGRadiother Oncol
- Locally Advanced Intrahepatic Cholangiocarcinoma: Complete Pathologic Response to Neoadjuvant Chemotherapy Followed by Left Hepatic Trisectionectomy and Caudate Lobectomy.Tran TB, Bal CK, Schaberg K, Longacre TA, Chatrath BS, Poultsides GADig Dis Sci
- Quantitative tracking of passage and 3D culture effects on chondrocyte and fibrochondrocyte gene expression.Son MS, Levenston MEJ Tissue Eng Regen Med
- Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT-D Trial.Williams LM, Korgaonkar MS, Song YC, Paton R, Eagles S, Goldstein-Piekarski A, Grieve SM, Harris AW, Usherwood T, Etkin ANeuropsychopharmacology
- Emerging Brain Morphologies from Axonal Elongation.Holland MA, Miller KE, Kuhl EAnn Biomed Eng
- Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments.Liang J, Xu W, Hsu YT, Yee AX, Chen L, Südhof TCMol Psychiatry
- The BRAIN Initiative: developing technology to catalyse neuroscience discovery.Jorgenson LA, Newsome WT, Anderson DJ, Bargmann CI, Brown EN, Deisseroth K, Donoghue JP, Hudson KL, Ling GS, MacLeish PR, Marder E, Normann RA, Sanes JR, Schnitzer MJ, Sejnowski TJ, Tank DW, Tsien RY, Ugurbil K, Wingfield JCPhilos Trans R Soc Lond B Biol Sci
- Randomized Trial of Studer Pouch versus T-Pouch Orthotopic Ileal Neobladder in Bladder Cancer Patients.Skinner EC, Fairey AS, Groshen S, Daneshmand S, Cai J, Miranda G, Skinner DGJ Urol
- Reply to B. O'Sullivan et al.Fakhry C, Zhang Q, Nguyen-Tan PF, Rosenthal D, El-Naggar AK, Garden AS, Soulieres D, Trotti A, Avizonis VN, Ridge JA, Harris J, Le QT, Gillison MJ Clin Oncol
- Iatrogenic Medial Patellar Instability: An Avoidable Injury.Sanchis-Alfonso V, Merchant ACArthroscopy
- B-1a lymphocytes attenuate insulin resistance.Shen L, Chng MH, Alonso MN, Yuan R, Winer DA, Engleman EGDiabetes
- Inflammation and hyperglycemia mediate Deaf1 splicing in the pancreatic lymph nodes via distinct pathways during type 1 diabetes.Yip L, Fuhlbrigge R, Taylor C, Creusot RJ, Nishikawa-Matsumura T, Whiting CC, Schartner JM, Akter R, von Herrath M, Fathman CGDiabetes
- Optimizing real time fMRI neurofeedback for therapeutic discovery and development.Stoeckel LE, Garrison KA, Ghosh S, Wighton P, Hanlon CA, Gilman JM, Greer S, Turk-Browne NB, deBettencourt MT, Scheinost D, Craddock C, Thompson T, Calderon V, Bauer CC, George M, Breiter HC, Whitfield-Gabrieli S, Gabrieli JD, LaConte SM, Hirshberg L, Brewer JA, Hampson M, Van Der Kouwe A, Mackey S, Evins AENeuroimage Clin
- Selection and characterization of a novel DNA aptamer for label-free fluorescence biosensing of ochratoxin A.McKeague M, Velu R, Hill K, Bardóczy V, Mészáros T, DeRosa MCToxins (Basel)
- Transcriptional profiling of belatacept and calcineurin inhibitor therapy in renal allograft recipients.Vitalone MJ, Ganguly B, Hsieh S, Latek R, Kulbokas EJ, Townsend R, Sarwal MMAm J Transplant
- The visiting internet Fiancé/ée (VIF): an emerging group of international travelers.Sofarelli TA, Birich HK, Hale DCJ Travel Med
- Opioids enhance CXCL1 expression and function after incision in mice.Sun Y, Sahbaie P, Liang D, Li W, Clark JDJ Pain
- Impact of insulin resistance on ventricular function in pulmonary arterial hypertension.Brunner NW, Skhiri M, Fortenko O, Hsi A, Haddad F, Khazeni N, Zamanian RTJ Heart Lung Transplant
- Nine patients with Xp22.31 microduplication, cognitive deficits, seizures, and talipes anomalies.Esplin ED, Li B, Slavotinek A, Novelli A, Battaglia A, Clark R, Curry C, Hudgins LAm J Med Genet A
Tropical Forest Fragmentation Affects Floral Visitors but Not the Structure of Individual-Based Palm-Pollinator Networks.
PLoS One. 2015;10(3):e0121275
Authors: Dáttilo W, Aguirre A, Quesada M, Dirzo R
Despite increasing knowledge about the effects of habitat loss on pollinators in natural landscapes, information is very limited regarding the underlying mechanisms of forest fragmentation affecting plant-pollinator interactions in such landscapes. Here, we used a network approach to describe the effects of forest fragmentation on the patterns of interactions involving the understory dominant palm Astrocaryum mexicanum (Arecaceae) and its floral visitors (including both effective and non-effective pollinators) at the individual level in a Mexican tropical rainforest landscape. Specifically, we asked: (i) Does fragment size affect the structure of individual-based plant-pollinator networks? (ii) Does the core of highly interacting visitor species change along the fragmentation size gradient? (iii) Does forest fragment size influence the abundance of effective pollinators of A. mexicanum? We found that fragment size did not affect the topological structure of the individual-based palm-pollinator network. Furthermore, while the composition of peripheral non-effective pollinators changed depending on fragment size, effective core generalist species of pollinators remained stable. We also observed that both abundance and variance of effective pollinators of male and female flowers of A. mexicanum increased with forest fragment size. These findings indicate that the presence of effective pollinators in the core of all forest fragments could keep the network structure stable along the gradient of forest fragmentation. In addition, pollination of A. mexicanum could be more effective in larger fragments, since the greater abundance of pollinators in these fragments may increase the amount of pollen and diversity of pollen donors between flowers of individual plants. Given the prevalence of fragmentation in tropical ecosystems, our results indicate that the current patterns of land use will have consequences on the underlying mechanisms of pollination in remnant forests.
PMID: 25826702 [PubMed - as supplied by publisher]
Crystal Structure of a Two-Subunit TrkA Octameric Gating Ring Assembly.
PLoS One. 2015;10(3):e0122512
Authors: Deller MC, Johnson HA, Miller MD, Spraggon G, Elsliger MA, Wilson IA, Lesley SA
The TM1088 locus of T. maritima codes for two proteins designated TM1088A and TM1088B, which combine to form the cytosolic portion of a putative Trk K+ transporter. We report the crystal structure of this assembly to a resolution of 3.45 Å. The high resolution crystal structures of the components of the assembly, TM1088A and TM1088B, were also determined independently to 1.50 Å and 1.55 Å, respectively. The TM1088 proteins are structurally homologous to each other and to other K+ transporter proteins, such as TrkA. These proteins form a cytosolic gating ring assembly that controls the flow of K+ ions across the membrane. TM1088 represents the first structure of a two-subunit Trk assembly. Despite the atypical genetics and chain organization of the TM1088 assembly, it shares significant structural homology and an overall quaternary organization with other single-subunit K+ gating ring assemblies. This structure provides the first structural insights into what may be an evolutionary ancestor of more modern single-subunit K+ gating ring assemblies.
PMID: 25826626 [PubMed - as supplied by publisher]
Fungi in Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis.
Semin Respir Crit Care Med. 2015 Apr;36(2):207-216
Authors: Moss RB
Bronchiectasis is a pathologic bronchial dilatation with loss of function that can result from multiple inflammatory and infectious injuries to the conducting airways of the lung. Molds, particularly the filamentous fungus Aspergillus fumigatus, have been implicated as a common cause of both cystic fibrosis (CF) and non-CF bronchiectasis, the latter primarily in patients with severe asthma. The pathogenesis of mold-associated bronchiectasis is usually due to atopic sensitization to mold allergens in the presence of active chronic endobronchial fungal infection with host innate and adaptive immune deviation to a Th2-dominated inflammation, a condition known as allergic bronchopulmonary aspergillosis (ABPA) (or allergic bronchopulmonary mycosis if a non-Aspergillus mold is implicated). Diagnostic criteria of ABPA continue to evolve, while treatment relies upon downregulation of the allergic inflammatory response with immunomodulatory agents and antifungal pharmacotherapy.
PMID: 25826588 [PubMed - as supplied by publisher]
Stress inoculation modeled in mice.
Transl Psychiatry. 2015;5:e537
Authors: Brockhurst J, Cheleuitte-Nieves C, Buckmaster CL, Schatzberg AF, Lyons DM
Stress inoculation entails intermittent exposure to mildly stressful situations that present opportunities to learn, practice and improve coping in the context of exposure psychotherapies and resiliency training. Here we investigate behavioral and hormonal aspects of stress inoculation modeled in mice. Mice randomized to stress inoculation or a control treatment condition were assessed for corticosterone stress hormone responses and behavior during open-field, object-exploration and tail-suspension tests. Stress inoculation training sessions that acutely increased plasma levels of corticosterone diminished subsequent immobility as a measure of behavioral despair on tail-suspension tests. Stress inoculation also decreased subsequent freezing in the open field despite comparable levels of thigmotaxis in mice from both treatment conditions. Stress inoculation subsequently decreased novel-object exploration latencies and reduced corticosterone responses to repeated restraint. These results demonstrate that stress inoculation acutely stimulates glucocorticoid signaling and then enhances subsequent indications of active coping behavior in mice. Unlike mouse models that screen for the absence of vulnerability to stress or presence of traits that occur in resilient individuals, stress inoculation training reflects an experience-dependent learning-like process that resembles interventions designed to build resilience in humans. Mouse models of stress inoculation may provide novel insights for new preventive strategies or therapeutic treatments of human psychiatric disorders that are triggered and exacerbated by stressful life events.
PMID: 25826112 [PubMed - as supplied by publisher]
Definitions of Cardiovascular Insufficiency and Relation to Outcomes in Critically Ill Newborn Infants.
Am J Perinatol. 2015 Mar 31;
Authors: Fernandez E, Watterberg KL, Faix RG, Yoder BA, Walsh MC, Lacy CB, Osborne KA, Das A, Kendrick DE, Stoll BJ, Poindexter BB, Laptook AR, Kennedy KA, Schibler K, Bell EF, Van Meurs KP, Frantz ID, Goldberg RN, Shankaran S, Carlo WA, Ehrenkranz RA, Sánchez PJ, Higgins RD, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
Background We previously reported on the overall incidence, management, and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short-term outcomes in term and late preterm newborn infants. Objective This study aims to evaluate how four definitions of CVI relate to short-term outcomes and death. Study Design The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short-term outcomes at discharge and four different definitions of CVI were further analyzed. Results All the four definitions were associated with greater number of days on MV and days on O2. The definition using a threshold blood pressure (BP) measurement alone was not associated with days of full feeding, days in the NICU or death. The definition based on the treatment of CVI was associated with all the outcomes including death. Conclusions The definition using a threshold BP alone was not consistently associated with adverse short-term outcomes. Using only a threshold BP to determine therapy may not improve outcomes.
PMID: 25825962 [PubMed - as supplied by publisher]
Integrative, dynamic structural biology at atomic resolution-it's about time.
Nat Methods. 2015 Mar 31;12(4):307-318
Authors: van den Bedem H, Fraser JS
Biomolecules adopt a dynamic ensemble of conformations, each with the potential to interact with binding partners or perform the chemical reactions required for a multitude of cellular functions. Recent advances in X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and other techniques are helping us realize the dream of seeing-in atomic detail-how different parts of biomolecules shift between functional substates using concerted motions. Integrative structural biology has advanced our understanding of the formation of large macromolecular complexes and how their components interact in assemblies by leveraging data from many low-resolution methods. Here, we review the growing opportunities for integrative, dynamic structural biology at the atomic scale, contending there is increasing synergistic potential between X-ray crystallography, NMR and computer simulations to reveal a structural basis for protein conformational dynamics at high resolution.
PMID: 25825836 [PubMed - as supplied by publisher]
Structure-based discovery of NANOG variant with enhanced properties to promote self-renewal and reprogramming of pluripotent stem cells.
Proc Natl Acad Sci U S A. 2015 Mar 30;
Authors: Hayashi Y, Caboni L, Das D, Yumoto F, Clayton T, Deller MC, Nguyen P, Farr CL, Chiu HJ, Miller MD, Elsliger MA, Deacon AM, Godzik A, Lesley SA, Tomoda K, Conklin BR, Wilson IA, Yamanaka S, Fletterick RJ
NANOG (from Irish mythology Tír na nÓg) transcription factor plays a central role in maintaining pluripotency, cooperating with OCT4 (also known as POU5F1 or OCT3/4), SOX2, and other pluripotency factors. Although the physiological roles of the NANOG protein have been extensively explored, biochemical and biophysical properties in relation to its structural analysis are poorly understood. Here we determined the crystal structure of the human NANOG homeodomain (hNANOG HD) bound to an OCT4 promoter DNA, which revealed amino acid residues involved in DNA recognition that are likely to be functionally important. We generated a series of hNANOG HD alanine substitution mutants based on the protein-DNA interaction and evolutionary conservation and determined their biological activities. Some mutant proteins were less stable, resulting in loss or decreased affinity for DNA binding. Overexpression of the orthologous mouse NANOG (mNANOG) mutants failed to maintain self-renewal of mouse embryonic stem cells without leukemia inhibitory factor. These results suggest that these residues are critical for NANOG transcriptional activity. Interestingly, one mutant, hNANOG L122A, conversely enhanced protein stability and DNA-binding affinity. The mNANOG L122A, when overexpressed in mouse embryonic stem cells, maintained their expression of self-renewal markers even when retinoic acid was added to forcibly drive differentiation. When overexpressed in epiblast stem cells or human induced pluripotent stem cells, the L122A mutants enhanced reprogramming into ground-state pluripotency. These findings demonstrate that structural and biophysical information on key transcriptional factors provides insights into the manipulation of stem cell behaviors and a framework for rational protein engineering.
PMID: 25825768 [PubMed - as supplied by publisher]
CD14-expressing cancer cells establish the inflammatory and proliferative tumor microenvironment in bladder cancer.
Proc Natl Acad Sci U S A. 2015 Mar 30;
Authors: Cheah MT, Chen JY, Sahoo D, Contreras-Trujillo H, Volkmer AK, Scheeren FA, Volkmer JP, Weissman IL
Nonresolving chronic inflammation at the neoplastic site is consistently associated with promoting tumor progression and poor patient outcomes. However, many aspects behind the mechanisms that establish this tumor-promoting inflammatory microenvironment remain undefined. Using bladder cancer (BC) as a model, we found that CD14-high cancer cells express higher levels of numerous inflammation mediators and form larger tumors compared with CD14-low cells. CD14 antigen is a glycosyl-phosphatidylinositol (GPI)-linked glycoprotein and has been shown to be critically important in the signaling pathways of Toll-like receptor (TLR). CD14 expression in this BC subpopulation of cancer cells is required for increased cytokine production and increased tumor growth. Furthermore, tumors formed by CD14-high cells are more highly vascularized with higher myeloid cell infiltration. Inflammatory factors produced by CD14-high BC cells recruit and polarize monocytes and macrophages to acquire immune-suppressive characteristics. In contrast, CD14-low BC cells have a higher baseline cell division rate than CD14-high cells. Importantly, CD14-high cells produce factors that further increase the proliferation of CD14-low cells. Collectively, we demonstrate that CD14-high BC cells may orchestrate tumor-promoting inflammation and drive tumor cell proliferation to promote tumor growth.
PMID: 25825750 [PubMed - as supplied by publisher]
Structural basis for the geometry-driven localization of a small protein.
Proc Natl Acad Sci U S A. 2015 Mar 30;
Authors: Gill RL, Castaing JP, Hsin J, Tan IS, Wang X, Huang KC, Tian F, Ramamurthi KS
In bacteria, certain shape-sensing proteins localize to differently curved membranes. During sporulation in Bacillus subtilis, the only convex (positively curved) surface in the cell is the forespore, an approximately spherical internal organelle. Previously, we demonstrated that SpoVM localizes to the forespore by preferentially adsorbing onto slightly convex membranes. Here, we used NMR and molecular dynamics simulations of SpoVM and a localization mutant (SpoVM(P9A)) to reveal that SpoVM's atypical amphipathic α-helix inserts deeply into the membrane and interacts extensively with acyl chains to sense packing differences in differently curved membranes. Based on binding to spherical supported lipid bilayers and Monte Carlo simulations, we hypothesize that SpoVM's membrane insertion, along with potential cooperative interactions with other SpoVM molecules in the lipid bilayer, drives its preferential localization onto slightly convex membranes. Such a mechanism, which is distinct from that used by high curvature-sensing proteins, may be widely conserved for the localization of proteins onto the surface of cellular organelles.
PMID: 25825747 [PubMed - as supplied by publisher]
Environmental tipping points significantly affect the cost-benefit assessment of climate policies.
Proc Natl Acad Sci U S A. 2015 Mar 30;
Authors: Cai Y, Judd KL, Lenton TM, Lontzek TS, Narita D
Most current cost-benefit analyses of climate change policies suggest an optimal global climate policy that is significantly less stringent than the level required to meet the internationally agreed 2 °C target. This is partly because the sum of estimated economic damage of climate change across various sectors, such as energy use and changes in agricultural production, results in only a small economic loss or even a small economic gain in the gross world product under predicted levels of climate change. However, those cost-benefit analyses rarely take account of environmental tipping points leading to abrupt and irreversible impacts on market and nonmarket goods and services, including those provided by the climate and by ecosystems. Here we show that including environmental tipping point impacts in a stochastic dynamic integrated assessment model profoundly alters cost-benefit assessment of global climate policy. The risk of a tipping point, even if it only has nonmarket impacts, could substantially increase the present optimal carbon tax. For example, a risk of only 5% loss in nonmarket goods that occurs with a 5% annual probability at 4 °C increase of the global surface temperature causes an immediate two-thirds increase in optimal carbon tax. If the tipping point also has a 5% impact on market goods, the optimal carbon tax increases by more than a factor of 3. Hence existing cost-benefit assessments of global climate policy may be significantly underestimating the needs for controlling climate change.
PMID: 25825719 [PubMed - as supplied by publisher]
Lipoprotein particles and size, total and high molecular weight adiponectin, and leptin in relation to incident coronary heart disease among severely obese postmenopausal women: The Women's Health Initiative Observational Study.
BBA Clin. 2015 Jun;3:243-250
Authors: Mackey RH, McTigue KM, Chang YF, Barinas-Mitchell E, Evans RW, Tinker LF, Lewis CE, Manson JE, Stefanick ML, Howard BV, Phillips LS, Liu S, Kulick D, Kuller LH
BACKGROUND: We hypothesized that higher concentrations of LDL particles (LDL-P) and leptin, and lower concentrations of HDL particles (HDL-P), and total and high molecular weight (HMW) adiponectin, would predict incident coronary heart disease (CHD) among severely obese postmenopausal women.
METHODS: In a case-cohort study nested in the Women's Health Initiative Observational Study, we sampled 677 of the 1852 white or black women with body mass index (BMI) ≥40 kg/m(2) and no prevalent cardiovascular disease (CVD), including all 124 cases of incident CHD over mean 5.0 year follow-up. Biomarkers were assayed on stored blood samples.
RESULTS: In multivariable-adjusted weighted Cox models, higher baseline levels of total and small LDL-P, and lower levels of total and medium HDL-P, and smaller mean HDL-P size were significantly associated with incident CHD. In contrast, large HDL-P levels were inversely associated with CHD only for women without diabetes, and higher total and HMW adiponectin levels and lower leptin levels were associated with CHD only for women with diabetes. Higher total LDL-P and lower HDL-P were associated with CHD risk independently of confounders including CV risk factors and other lipoprotein measures, with adjusted HR (95%CIs) of 1.55(1.28, 1.88) and (0.70 (0.57, 0.85), respectively, and similar results for medium HDL-P.
CONCLUSIONS: Higher CHD risk among severely obese postmenopausal women is strongly associated with modifiable concentrations of LDL-P and HDL-P, independent of diabetes, smoking, hypertension, physical activity, BMI and waist circumference.
GENERAL SIGNIFICANCE: Severely obese postmenopausal women should be considered high risk candidates for lipid lowering therapy.
PMID: 25825692 [PubMed - as supplied by publisher]
Theranostic mesoporous silica nanoparticles biodegrade after pro-survival drug delivery and ultrasound/magnetic resonance imaging of stem cells.
Authors: Kempen PJ, Greasley S, Parker KA, Campbell JL, Chang HY, Jones JR, Sinclair R, Gambhir SS, Jokerst JV
Increasing cell survival in stem cell therapy is an important challenge for the field of regenerative medicine. Here, we report theranostic mesoporous silica nanoparticles that can increase cell survival through both diagnostic and therapeutic approaches. First, the nanoparticle offers ultrasound and MRI signal to guide implantation into the peri-infarct zone and away from the most necrotic tissue. Second, the nanoparticle serves as a slow release reservoir of insulin-like growth factor (IGF)-a protein shown to increase cell survival. Mesenchymal stem cells labeled with these nanoparticles had detection limits near 9000 cells with no cytotoxicity at the 250 µg/mL concentration required for labeling. We also studied the degradation of the nanoparticles and showed that they clear from cells in approximately 3 weeks. The presence of IGF increased cell survival up to 40% (p<0.05) versus unlabeled cells under in vitro serum-free culture conditions.
PMID: 25825602 [PubMed - in process]
Organoid modeling for cancer precision medicine.
Genome Med. 2015;7(1):32
Authors: Cantrell MA, Kuo CJ
Three-dimensional organotypic culture models show great promise as a tool for cancer precision medicine, with potential applications for oncogene modeling, gene discovery and chemosensitivity studies.
PMID: 25825593 [PubMed]
Evidence-based guideline summary: Evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine.
Neurology. 2015 Mar 31;84(13):1369-78
Authors: Kang PB, Morrison L, Iannaccone ST, Graham RJ, Bönnemann CG, Rutkowski A, Hornyak J, Wang CH, North K, Oskoui M, Getchius TS, Cox JA, Hagen EE, Gronseth G, Griggs RC
OBJECTIVE: To delineate optimal diagnostic and therapeutic approaches to congenital muscular dystrophy (CMD) through a systematic review and analysis of the currently available literature.
METHODS: Relevant, peer-reviewed research articles were identified using a literature search of the MEDLINE, EMBASE, and Scopus databases. Diagnostic and therapeutic data from these articles were extracted and analyzed in accordance with the American Academy of Neurology classification of evidence schemes for diagnostic, prognostic, and therapeutic studies. Recommendations were linked to the strength of the evidence, other related literature, and general principles of care.
RESULTS: The geographic and ethnic backgrounds, clinical features, brain imaging studies, muscle imaging studies, and muscle biopsies of children with suspected CMD help predict subtype-specific diagnoses. Genetic testing can confirm some subtype-specific diagnoses, but not all causative genes for CMD have been described. Seizures and respiratory complications occur in specific subtypes. There is insufficient evidence to determine the efficacy of various treatment interventions to optimize respiratory, orthopedic, and nutritional outcomes, and more data are needed regarding complications.
RECOMMENDATIONS: Multidisciplinary care by experienced teams is important for diagnosing and promoting the health of children with CMD. Accurate assessment of clinical presentations and genetic data will help in identifying the correct subtype-specific diagnosis in many cases. Multiorgan system complications occur frequently; surveillance and prompt interventions are likely to be beneficial for affected children. More research is needed to fill gaps in knowledge regarding this category of muscular dystrophies.
PMID: 25825463 [PubMed - in process]
Ability To Develop Broadly Neutralizing HIV-1 Antibodies Is Not Restricted by the Germline Ig Gene Repertoire.
J Immunol. 2015 Mar 30;
Authors: Scheepers C, Shrestha RK, Lambson BE, Jackson KJ, Wright IA, Naicker D, Goosen M, Berrie L, Ismail A, Garrett N, Abdool Karim Q, Abdool Karim SS, Moore PL, Travers SA, Morris L
The human Ig repertoire is vast, producing billions of unique Abs from a limited number of germline Ig genes. The IgH V region (IGHV) is central to Ag binding and consists of 48 functional genes. In this study, we analyzed whether HIV-1-infected individuals who develop broadly neutralizing Abs show a distinctive germline IGHV profile. Using both 454 and Illumina technologies, we sequenced the IGHV repertoire of 28 HIV-infected South African women from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 002 and 004 cohorts, 13 of whom developed broadly neutralizing Abs. Of the 259 IGHV alleles identified in this study, approximately half were not found in the International Immunogenetics Database (IMGT). This included 85 entirely novel alleles and 38 alleles that matched rearranged sequences in non-IMGT databases. Analysis of the rearranged H chain V region genes of mAbs isolated from seven of these women, as well as previously isolated broadly neutralizing Abs from other donors, provided evidence that at least eight novel or non-IMGT alleles contributed to functional Abs. Importantly, we found that, despite a wide range in the number of IGHV alleles in each individual, including alleles used by known broadly neutralizing Abs, there were no significant differences in germline IGHV repertoires between individuals who do and do not develop broadly neutralizing Abs. This study reports novel IGHV repertoires and highlights the importance of a fully comprehensive Ig database for germline gene usage prediction. Furthermore, these data suggest a lack of genetic bias in broadly neutralizing Ab development in HIV-1 infection, with positive implications for HIV vaccine design.
PMID: 25825450 [PubMed - as supplied by publisher]
Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.
J Allergy Clin Immunol. 2015 Mar 27;
Authors: Xia M, Viera-Hutchins L, Garcia-Lloret M, Noval Rivas M, Wise P, McGhee SA, Chatila ZK, Daher N, Sioutas C, Chatila TA
BACKGROUND: Traffic-related particulate matter (PM) has been linked to a heightened incidence of asthma and allergic diseases. However, the molecular mechanisms by which PM exposure promotes allergic diseases remain elusive.
OBJECTIVE: We sought to determine the expression, function, and regulation of pathways involved in promotion of allergic airway inflammation by PM.
METHODS: We used gene expression transcriptional profiling, in vitro culture assays, and in vivo murine models of allergic airway inflammation.
RESULTS: We identified components of the Notch pathway, most notably Jagged 1 (Jag1), as targets of PM induction in human monocytes and murine dendritic cells. PM, especially ultrafine particles, upregulated TH cytokine levels, IgE production, and allergic airway inflammation in mice in a Jag1- and Notch-dependent manner, especially in the context of the proasthmatic IL-4 receptor allele Il4raR576. PM-induced Jag1 expression was mediated by the aryl hydrocarbon receptor (AhR), which bound to and activated AhR response elements in the Jag1 promoter. Pharmacologic antagonism of AhR or its lineage-specific deletion in CD11c(+) cells abrogated the augmentation of airway inflammation by PM.
CONCLUSION: PM activates an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with proasthmatic alleles.
PMID: 25825216 [PubMed - as supplied by publisher]
Noninvasive pulmonary nodule elastometry by CT and deformable image registration.
Radiother Oncol. 2015 Mar 27;
Authors: Negahdar M, Fasola CE, Yu AS, von Eyben R, Yamamoto T, Diehn M, Fleischmann D, Tian L, Loo BW, Maxim PG
BACKGROUND AND PURPOSE: To develop a noninvasive method for determining malignant pulmonary nodule (MPN) elasticity, and compare it against expert dual-observer manual contouring.
METHODS AND MATERIALS: We analyzed breath-hold images at extreme tidal volumes of 23 patients with 30 MPN treated with stereotactic ablative radiotherapy. Deformable image registration (DIR) was applied to the breath-hold images to determine the volumes of the MPNs and a ring of surrounding lung tissue (ring) in each state. MPNs were also manually delineated on deep inhale and exhale images by two observers. Volumes were compared between observers and DIR by Dice similarity. Elasticity was defined as the absolute value of the volume ratio of the MPN minus one normalized to that of the ring.
RESULTS: For all 30 tumors the Dice coefficient was 0.79±0.07 and 0.79±0.06 between DIR with observers 1 and 2, respectively, close to the inter-observer Dice value, 0.81±0.1. The elasticity of MPNs was 1.24±0.26, demonstrating that volume change of the MPN was less than that of the surrounding lung.
CONCLUSION: We developed a noninvasive CT elastometry method based on DIR that measures the elasticity of biopsy-proven MPN. Our future direction would be to develop this method to distinguish malignant from benign nodules.
PMID: 25824979 [PubMed - as supplied by publisher]
Locally Advanced Intrahepatic Cholangiocarcinoma: Complete Pathologic Response to Neoadjuvant Chemotherapy Followed by Left Hepatic Trisectionectomy and Caudate Lobectomy.
Dig Dis Sci. 2015 Apr 1;
Authors: Tran TB, Bal CK, Schaberg K, Longacre TA, Chatrath BS, Poultsides GA
PMID: 25824976 [PubMed - as supplied by publisher]
Quantitative tracking of passage and 3D culture effects on chondrocyte and fibrochondrocyte gene expression.
J Tissue Eng Regen Med. 2015 Mar 30;
Authors: Son MS, Levenston ME
Success in cartilage and fibrocartilage tissue engineering relies heavily on using an appropriate cell source. Many different cell sources have been identified, including primary and stem cells, along with experimental strategies to obtain the required number of cells or to induce chondrogenesis. However, no definitive method exists to quantitatively evaluate the similarity of the resulting cell phenotypes to those of the native cells between candidate strategies. In this study, we develop an integrative approach to enable such evaluations by deriving, from gene expression profiles, two quantitative metrics representing the nearest location within the range of native cell phenotypes and the deviation from it. As an example application to evaluating potential cell sources for cartilage or meniscus tissue engineering, we examine phenotypic changes of juvenile and adult articular chondrocytes and fibrochondrocytes across multiple passages and subsequent 3D culture. A substantial change was observed in cell phenotype due to the isolation process itself, followed by a clear progression toward the outer meniscal cell phenotype with passage. The new metrics also indicated that 3D culture moderately reduced the passage-induced deviation from the native meniscal phenotypes for juvenile chondrocytes and adult fibrochondrocytes, which was not obvious through examination of individual gene expressions. However, brief 3D culture alone did not move any of the cells towards an inner meniscal phenotype, the most relevant target for meniscal tissue engineering. This integrative approach of examining and combining multiple gene expressions can be used to evaluate various other tissue-engineering strategies to direct cells toward the desired phenotype. Copyright © 2015 John Wiley & Sons, Ltd.
PMID: 25824488 [PubMed - as supplied by publisher]
Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT-D Trial.
Neuropsychopharmacology. 2015 Mar 31;
Authors: Williams LM, Korgaonkar MS, Song YC, Paton R, Eagles S, Goldstein-Piekarski A, Grieve SM, Harris AW, Usherwood T, Etkin A
Although the cost of poor treatment outcomes of depression is staggering we do not yet have clinically useful methods for selecting the most effective antidepressant for each depressed person. Emotional brain activation is altered in MDD and implicated in treatment response. Identifying which aspects of emotional brain activation are predictive of general and specific responses to antidepressants may help clinicians and patients when making treatment decisions. We examined whether amygdala activation probed by emotion stimuli is a general or differential predictor of response to three commonly prescribed antidepressants, using functional magnetic resonance imaging (fMRI). A test-retest design was used to assess patients with major depressive disorder (MDD) in an academic setting as part of the International Study to Predict Optimized Treatment in Depression. 80 MDD outpatients were scanned pre-treatment and 8 weeks after randomization to the selective serotonin reuptake inhibitors escitalopram and sertraline and the serotonin-norepinephrine reuptake inhibitor, venlafaxine-extended release (XR). 34 matched controls were scanned at the same timepoints. We quantified the blood oxygen level-dependent signal of the amygdala during subliminal and supraliminal viewing of facial expressions of emotion. Response to treatment was defined by >=50% symptom improvement on the 17-item Hamilton Depression Rating Scale. Pre-treatment amygdala hypo-reactivity to subliminal happy and threat was a general predictor of treatment response, regardless of medication type (cohen's d effect size.63 to.77; classification accuracy, 75%). Responders showed hypo-reactivity compared to controls at baseline, and an increase toward "normalization" post-treatment. Pre-treatment amygdala reactivity to subliminal sadness was a differential moderator of non-response to venlafaxine-XR (cohen's d effect size 1.5; classification accuracy, 81%). Non-responders to venlafaxine-XR showed pre-treatment hyper-reactivity which progressed to hypo-reactivity rather than normalization post-treatment and hypo-reactivity post-treatment was abnormal compared to controls. Impaired amygdala activation has not previously been highlighted in the general versus differential prediction of antidepressant outcomes. Amygdala hypo-reactivity to emotions signaling reward and threat predicts the general capacity to respond to antidepressants. Amygdala hyper-reactivity to sad emotion is involved in a specific non-response to a serotonin-norepinephrine reuptake inhibitor. The findings suggest amygdala probes may help inform the personal selection of antidepressant treatments.Neuropsychopharmacology accepted article preview online, 31 March 2015. doi:10.1038/npp.2015.89.
PMID: 25824424 [PubMed - as supplied by publisher]
Emerging Brain Morphologies from Axonal Elongation.
Ann Biomed Eng. 2015 Mar 31;
Authors: Holland MA, Miller KE, Kuhl E
Understanding the characteristic morphology of our brain remains a challenging, yet important task in human evolution, developmental biology, and neurosciences. Mathematical modeling shapes our understanding of cortical folding and provides functional relations between cortical wavelength, thickness, and stiffness. Yet, current mathematical models are phenomenologically isotropic and typically predict non-physiological, periodic folding patterns. Here we establish a mechanistic model for cortical folding, in which macroscopic changes in white matter volume are a natural consequence of microscopic axonal growth. To calibrate our model, we consult axon elongation experiments in chick sensory neurons. We demonstrate that a single parameter, the axonal growth rate, explains a wide variety of in vitro conditions including immediate axonal thinning and gradual thickness restoration. We embed our axonal growth model into a continuum model for brain development using axonal orientation distributions motivated by diffusion spectrum imaging. Our simulations suggest that white matter anisotropy-as an emergent property from directional axonal growth-intrinsically induces symmetry breaking, and predicts more physiological, less regular morphologies with regionally varying gyral wavelengths and sulcal depths. Mechanistic modeling of brain development could establish valuable relationships between brain connectivity, brain anatomy, and brain function.
PMID: 25824370 [PubMed - as supplied by publisher]
Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments.
Mol Psychiatry. 2015 Mar 31;
Authors: Liang J, Xu W, Hsu YT, Yee AX, Chen L, Südhof TC
Abnormal activity in the medial prefrontal cortex (mPFC) is consistently observed in neuropsychiatric disorders, but the mechanisms involved remain unclear. Chronic aberrant excitation and/or inhibition of mPFC neurons were proposed to cause cognitive impairments. However, direct evidence for this hypothesis is lacking because it is technically challenging to control synaptic properties in a chronic and locally restricted, yet specific, manner. Here, we generated conditional knockout (cKO) mice of neuroligin-2 (Nlgn2), a postsynaptic cell-adhesion molecule of inhibitory synapses linked to neuropsychiatric disorders. cKO of Nlgn2 in adult mPFC rendered Nlgn2 protein undetectable after already 2-3 weeks, but induced major reductions in synaptic inhibition after only 6-7 weeks, and caused parallel impairments in anxiety, fear memory and social interaction behaviors. Moreover, cKO of Nlgn2 severely impaired behavioral stimulation of immediate-early gene expression in the mPFC, suggesting that chronic reduction in synaptic inhibition uncoupled the mPFC from experience-dependent inputs. Our results indicate that Nlgn2 is required for continuous maintenance of inhibitory synapses in the adult mPFC, and that chronic impairment of local inhibition disengages the mPFC from its cognitive functions by partially uncoupling the mPFC from experience-induced inputs.Molecular Psychiatry advance online publication, 31 March 2015; doi:10.1038/mp.2015.31.
PMID: 25824299 [PubMed - as supplied by publisher]
The BRAIN Initiative: developing technology to catalyse neuroscience discovery.
Philos Trans R Soc Lond B Biol Sci. 2015 May 19;370(1668)
Authors: Jorgenson LA, Newsome WT, Anderson DJ, Bargmann CI, Brown EN, Deisseroth K, Donoghue JP, Hudson KL, Ling GS, MacLeish PR, Marder E, Normann RA, Sanes JR, Schnitzer MJ, Sejnowski TJ, Tank DW, Tsien RY, Ugurbil K, Wingfield JC
The evolution of the field of neuroscience has been propelled by the advent of novel technological capabilities, and the pace at which these capabilities are being developed has accelerated dramatically in the past decade. Capitalizing on this momentum, the United States launched the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative to develop and apply new tools and technologies for revolutionizing our understanding of the brain. In this article, we review the scientific vision for this initiative set forth by the National Institutes of Health and discuss its implications for the future of neuroscience research. Particular emphasis is given to its potential impact on the mapping and study of neural circuits, and how this knowledge will transform our understanding of the complexity of the human brain and its diverse array of behaviours, perceptions, thoughts and emotions.
PMID: 25823863 [PubMed - as supplied by publisher]
Randomized Trial of Studer Pouch versus T-Pouch Orthotopic Ileal Neobladder in Bladder Cancer Patients.
J Urol. 2015 Mar 27;
Authors: Skinner EC, Fairey AS, Groshen S, Daneshmand S, Cai J, Miranda G, Skinner DG
BACKGROUND: the need to prevent reflux in the construction of an orthotopic ileal neobladder (ONB) is controversial. We designed the USC-STAR trial to determine whether the T-pouch neobladder that included an anti-reflux mechanism was superior to the Studer Pouch in patients with bladder cancer undergoing radical cystectomy.
METHODS: This single center, randomized, controlled trial recruited clinically non-metastatic BC patients scheduled to undergo radical cystectomy with neobladder. Eligible patients were randomly assigned to undergo T-Pouch or Studer ONB. Treatment assignment was not masked. The primary endpoint was change in renal function from baseline to 3 years. The CKD-EPI equation was used to calculate the eGFR.
RESULTS: Between February, 2002 and November, 2009, 237 patients were randomly assigned to T-pouch ONB and 247 to Studer ONB. Baseline characteristics did not differ between groups. Between baseline and 3 years, eGFR decreased by 6.4 ml/min/1.73m2 in the Studer group and 6.6 ml/min/1.73m2 in the T-Pouch group (p=0.35). Multivariable analysis showed that type of ONB was not independently associated with 3-year renal function (p=0.63); however, baseline eGFR, age, and urinary tract obstruction were independently associated with 3-year decline in renal function. Cumulative risk of UTI and overall late complications were not different between the groups but the T-pouch was associated with an increased risk of secondary diversion-related surgeries.
CONCLUSIONS: T-Pouch ONB with an antireflux mechanism did not prevent a moderate reduction in renal function observed at 3 years compared to the Studer Pouch, but did result in an increase in diversion-related secondary surgical procedures.
PMID: 25823791 [PubMed - as supplied by publisher]
Reply to B. O'Sullivan et al.
J Clin Oncol. 2015 Mar 30;
Authors: Fakhry C, Zhang Q, Nguyen-Tan PF, Rosenthal D, El-Naggar AK, Garden AS, Soulieres D, Trotti A, Avizonis VN, Ridge JA, Harris J, Le QT, Gillison M
PMID: 25823732 [PubMed - as supplied by publisher]
Iatrogenic Medial Patellar Instability: An Avoidable Injury.
Arthroscopy. 2015 Mar 27;
Authors: Sanchis-Alfonso V, Merchant AC
Iatrogenic medial patellar instability is a specific condition that frequently causes incapacitating anterior knee pain, severe disability, and serious psychological problems. The diagnosis should be suspected in a patient who has undergone previous patellar realignment surgery that has made the pain worse. The diagnosis can be established by physical examination and simple therapeutic tests (e.g., "reverse" McConnell taping) and confirmed by imaging techniques. This iatrogenic condition should no longer exist and could almost be eliminated by avoiding over-release of the lateral retinaculum.
PMID: 25823671 [PubMed - as supplied by publisher]
B-1a lymphocytes attenuate insulin resistance.
Diabetes. 2015 Feb;64(2):593-603
Authors: Shen L, Chng MH, Alonso MN, Yuan R, Winer DA, Engleman EG
Obesity-associated insulin resistance, a common precursor of type 2 diabetes, is characterized by chronic inflammation of tissues, including visceral adipose tissue (VAT). Here we show that B-1a cells, a subpopulation of B lymphocytes, are novel and important regulators of this process. B-1a cells are reduced in frequency in obese high-fat diet (HFD)-fed mice, and EGFP interleukin-10 (IL-10) reporter mice show marked reductions in anti-inflammatory IL-10 production by B cells in vivo during obesity. In VAT, B-1a cells are the dominant producers of B cell-derived IL-10, contributing nearly half of the expressed IL-10 in vivo. Adoptive transfer of B-1a cells into HFD-fed B cell-deficient mice rapidly improves insulin resistance and glucose tolerance through IL-10 and polyclonal IgM-dependent mechanisms, whereas transfer of B-2 cells worsens metabolic disease. Genetic knockdown of B cell-activating factor (BAFF) in HFD-fed mice or treatment with a B-2 cell-depleting, B-1a cell-sparing anti-BAFF antibody attenuates insulin resistance. These findings establish B-1a cells as a new class of immune regulators that maintain metabolic homeostasis and suggest manipulation of these cells as a potential therapy for insulin resistance.
PMID: 25249575 [PubMed - indexed for MEDLINE]
Inflammation and hyperglycemia mediate Deaf1 splicing in the pancreatic lymph nodes via distinct pathways during type 1 diabetes.
Diabetes. 2015 Feb;64(2):604-17
Authors: Yip L, Fuhlbrigge R, Taylor C, Creusot RJ, Nishikawa-Matsumura T, Whiting CC, Schartner JM, Akter R, von Herrath M, Fathman CG
Peripheral tolerance is partially controlled by the expression of peripheral tissue antigens (PTAs) in lymph node stromal cells (LNSCs). We previously identified a transcriptional regulator, deformed epidermal autoregulatory factor 1 (Deaf1), that can regulate PTA expression in LNSCs of the pancreatic lymph nodes (PLNs). During the pathogenesis of type 1 diabetes (T1D), Deaf1 is spliced to form the dominant-negative isoform Deaf1-Var1. Here we show that Deaf1-Var1 expression correlates with the severity of disease in NOD mice and is reduced in the PLNs of mice that do not develop hyperglycemia. Inflammation and hyperglycemia independently drive Deaf1 splicing through activation of the splicing factors Srsf10 and Ptbp2, respectively. Inflammation induced by injection of activated splenocytes increased Deaf1-Var1 and Srsf10, but not Ptbp2, in the PLNs of NOD.SCID mice. Hyperglycemia induced by treatment with the insulin receptor agonist S961 increased Deaf1-Var1 and Ptbp2, but not Srsf10, in the PLNs of NOD.B10 and NOD mice. Overexpression of PTBP2 and/or SRSF10 also increased human DEAF1-VAR1 and reduced PTA expression in HEK293T cells. These data suggest that during the progression of T1D, inflammation and hyperglycemia mediate the splicing of DEAF1 and loss of PTA expression in LNSCs by regulating the expression of SRSF10 and PTBP2.
PMID: 25187368 [PubMed - indexed for MEDLINE]
Optimizing real time fMRI neurofeedback for therapeutic discovery and development.
Neuroimage Clin. 2014;5:245-55
Authors: Stoeckel LE, Garrison KA, Ghosh S, Wighton P, Hanlon CA, Gilman JM, Greer S, Turk-Browne NB, deBettencourt MT, Scheinost D, Craddock C, Thompson T, Calderon V, Bauer CC, George M, Breiter HC, Whitfield-Gabrieli S, Gabrieli JD, LaConte SM, Hirshberg L, Brewer JA, Hampson M, Van Der Kouwe A, Mackey S, Evins AE
While reducing the burden of brain disorders remains a top priority of organizations like the World Health Organization and National Institutes of Health, the development of novel, safe and effective treatments for brain disorders has been slow. In this paper, we describe the state of the science for an emerging technology, real time functional magnetic resonance imaging (rtfMRI) neurofeedback, in clinical neurotherapeutics. We review the scientific potential of rtfMRI and outline research strategies to optimize the development and application of rtfMRI neurofeedback as a next generation therapeutic tool. We propose that rtfMRI can be used to address a broad range of clinical problems by improving our understanding of brain-behavior relationships in order to develop more specific and effective interventions for individuals with brain disorders. We focus on the use of rtfMRI neurofeedback as a clinical neurotherapeutic tool to drive plasticity in brain function, cognition, and behavior. Our overall goal is for rtfMRI to advance personalized assessment and intervention approaches to enhance resilience and reduce morbidity by correcting maladaptive patterns of brain function in those with brain disorders.
PMID: 25161891 [PubMed - indexed for MEDLINE]
Selection and characterization of a novel DNA aptamer for label-free fluorescence biosensing of ochratoxin A.
Toxins (Basel). 2014 Aug;6(8):2435-52
Authors: McKeague M, Velu R, Hill K, Bardóczy V, Mészáros T, DeRosa MC
Nucleic acid aptamers are emerging as useful molecular recognition tools for food safety monitoring. However, practical and technical challenges limit the number and diversity of available aptamer probes that can be incorporated into novel sensing schemes. This work describes the selection of novel DNA aptamers that bind to the important food contaminant ochratoxin A (OTA). Following 15 rounds of in vitro selection, sequences were analyzed for OTA binding. Two of the isolated aptamers demonstrated high affinity binding and selectivity to this mycotoxin compared to similar food adulterants. These sequences, as well as a truncated aptamer (minimal sequence required for binding), were incorporated into a SYBR® Green I fluorescence-based OTA biosensing scheme. This label-free detection platform is capable of rapid, selective, and sensitive OTA quantification with a limit of detection of 9 nM and linear quantification up to 100 nM.
PMID: 25153252 [PubMed - indexed for MEDLINE]
Transcriptional profiling of belatacept and calcineurin inhibitor therapy in renal allograft recipients.
Am J Transplant. 2014 Aug;14(8):1912-21
Authors: Vitalone MJ, Ganguly B, Hsieh S, Latek R, Kulbokas EJ, Townsend R, Sarwal MM
Calcineurin inhibitor (CNI) use may lead to allograft injury and compromised renal function. Gene expression profiles of 12-month kidney biopsies from a Phase 3 study of belatacept and a CNI comparator, cyclosporine (CsA), were compared with expression profiles of a set of historical, demographically matched, preimplantation control biopsies. Gene set enrichment analysis was used to test each set of differentially expressed genes (DEGs) for the enrichment of an in vitro-derived CNI toxicity (CNIT) gene set and published gene sets associated with chronic allograft injury (CAI), immune modulation and tissue remodeling. The unique set of genes differentially expressed in CNI biopsies compared with preimplantation controls was enriched for genes associated with fibrosis, early tubulointerstitial damage and in vitro CNIT. The DEGs from belatacept biopsies were not enriched for the CNIT genes but, instead, exhibited enrichment for gene sets associated with immune response and tissue remodeling. A combined analysis of DEGs across both treatment groups identified select solute transporter and cellular differentiation genes whose expression at 12 months correlated with renal function at 36 months. These results provide mechanistic insights into the reduced CAI and higher renal function observed in belatacept- versus CsA-treated patients.
PMID: 24954576 [PubMed - indexed for MEDLINE]
The visiting internet Fiancé/ée (VIF): an emerging group of international travelers.
J Travel Med. 2014 Sep-Oct;21(5):349-51
Authors: Sofarelli TA, Birich HK, Hale DC
Here we describe an emerging category of travelers called the Visiting Internet Fiancé/ée (VIF), characterized by their travel to pursue a romantic relationship with an individual they have only encountered online. The VIF is not well identified in travel medicine literature despite having a higher risk for several travel-related issues including sexually transmitted infections, monetary fraud, and international scams. We also propose specific counseling interventions designed to minimize the adverse outcomes faced by the VIF traveler.
PMID: 24888904 [PubMed - indexed for MEDLINE]
Opioids enhance CXCL1 expression and function after incision in mice.
J Pain. 2014 Aug;15(8):856-66
Authors: Sun Y, Sahbaie P, Liang D, Li W, Clark JD
UNLABELLED: Chronic opioid consumption increases postoperative pain. Epigenetic changes related to chronic opioid use and surgical incision may be partially responsible for this enhancement. The CXCL1/CXCR2 signaling pathway, implicated in several pain models, is known to be epigenetically regulated via histone acetylation. The current study was designed to investigate the role of CXCL1/CXCR2 signaling in opioid-enhanced incisional sensitization and to elucidate the possible epigenetic mechanism underlying CXCL1/CXCR2 pathway-mediated regulation of nociceptive sensitization in mice. Chronic morphine treatment generated mechanical and thermal nociceptive sensitization and also significantly exacerbated incision-induced mechanical allodynia. Peripheral but not central messenger RNA levels of CXCL1 and CXCR2 were increased after incision. The source of peripheral CXCL1 appeared to be wound area neutrophils. Histone H3 subunit acetylated at the lysine 9 position (AcH3K9) was increased in infiltrating dermal neutrophils after incision and was further increased in mice with chronic morphine treatment. The association of AcH3K9 with the promoter region of CXCL1 was enhanced in mice after chronic morphine treatment. The increase in CXCL1 near wounds caused by chronic morphine pretreatment was mimicked by pharmacologic inhibition of histone deacetylation. Finally, local injection of CXCL1 induced mechanical sensitivity in naive mice, whereas blocking CXCR2 reversed mechanical hypersensitivity after hind paw incision.
PERSPECTIVE: Peripheral CXCL1/CXCR2 signaling helps to control nociceptive sensitization after incision, and epigenetic regulation of CXCL1 expression explains in part opioid-enhanced incisional allodynia in mice. These results suggest that targeting CXCL1/CXCR2 signaling may be useful in treating nociceptive sensitization, particularly for postoperative pain in chronic opioid-consuming patients.
PMID: 24887006 [PubMed - indexed for MEDLINE]
Impact of insulin resistance on ventricular function in pulmonary arterial hypertension.
J Heart Lung Transplant. 2014 Jul;33(7):721-6
Authors: Brunner NW, Skhiri M, Fortenko O, Hsi A, Haddad F, Khazeni N, Zamanian RT
BACKGROUND: Insulin resistance (IR) is an independent prognostic marker in pulmonary arterial hypertension (PAH), although the mechanism by which it engenders risk is unknown. We prospectively investigated the clinical, laboratory, hemodynamic, and echocardiographic characteristics of insulin-sensitive (IS) and IR patients with PAH.
METHODS: This was a prospective cohort study including well-phenotyped patients with PAH proven at cardiac catheterization. Patients were classified as IS or IR on the basis of the well-validated triglyceride/high-density lipoprotein-cholesterol ratio. Clinical, laboratory, and hemodynamic characteristics were compared between cohorts. Distance walked on the 6-minute walk test (6MWT) and echocardiograms were compared between IS and IR for the sub-set of patients that had these tests within 1 month of cardiac catheterization.
RESULTS: Of the 111 PAH patients enrolled, 59 were IS, 25 were IR, and 27 were classified as indeterminate. Mean age was 45.8 ± 15.0 years. IR was associated with worse New York Heart Association class (p = 0.02). There were no differences in hemodynamics, biomarkers, 6MWT distance, or parameters of right ventricular function (i.e., tricuspid annular plane systolic excursion, myocardial performance index, and fractional area change) between groups. Despite similar systemic vascular resistance, parameters of left ventricular diastolic function were more favorable for IS vs IR, including mitral inflow E wave velocity (82 ± 17 vs. 64 ± 19 msec, p = 0.02), E/A ratio (1.2 ± 0.4 vs. 0.8 ± 0.2, p = 0.01), and lateral mitral valve E' velocity (13.9 ± 3.5 vs. 10.4 ± 2.2 msec, p = 0.01).
CONCLUSIONS: IR is associated with worse functional class and diastology compared with IS in PAH, although other prognostic parameters are similar.
PMID: 24819985 [PubMed - indexed for MEDLINE]
Nine patients with Xp22.31 microduplication, cognitive deficits, seizures, and talipes anomalies.
Am J Med Genet A. 2014 Aug;164A(8):2097-103
Authors: Esplin ED, Li B, Slavotinek A, Novelli A, Battaglia A, Clark R, Curry C, Hudgins L
Comparative genomic hybridization (CGH) arrays have significantly changed the approach to identifying genetic alterations causing intellectual disability and congenital anomalies. Several studies have described the microduplication of Xp22.31, involving the STS gene. In such reports characteristic features and pathogenicity of Xp22.31 duplications remains a subject of debate. Here we present a series of nine previously unreported individuals with Xp22.31 duplications, found through microarray analysis in the course of genetic workup for developmental delay, associated with a combination of talipes anomalies, seizures and/or feeding difficulties. The size of the Xp22.31 duplications ranged from 294 kb to 1.6 Mb. We show a comparison of the breakpoints, inheritance and clinical phenotype, and a review of the literature. This clinically detailed series of Xp22.31 duplication patients provides evidence that the Xp22.31 duplication contributes to a common phenotype.
PMID: 24800990 [PubMed - indexed for MEDLINE]
Access restricted to Stanford community
Can't find it?
Look if we have it in print:
- All Biomedical Resources
- Specialty Portals
- Obstetrics & Gynecology
- Biomedical Ethics
- Palliative Care
- Comparative Medicine
- Consumer Health
- Emergency Medicine
- Global Health
- Physical Medicine & Rehab.
- Infectious Diseases
- Internal Medicine
- LPCH Heart Center Nursing
- Reference Desk
- Medical Education
- Spiritual Care
- Multicultural Health
- Student IL Materials
- Classes & Tutorials
- Using the Library
- About Lane
- How To