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- Fiber-Optic System for Dual-Modality Imaging of Glucose Probes 18F-FDG and 6-NBDG in Atherosclerotic Plaques.Zaman RT, Kosuge H, Pratx G, Carpenter C, Xing L, McConnell MVPLoS One
- A Universal Approach to Prepare Reagents for DNA-Assisted Protein Analysis.Yan J, Gu GJ, Jost C, Hammond M, Plückthun A, Landegren U, Kamali-Moghaddam MPLoS One
- The Association of the Vanin-1 N131S Variant with Blood Pressure Is Mediated by Endoplasmic Reticulum-Associated Degradation and Loss of Function.Wang YJ, Tayo BO, Bandyopadhyay A, Wang H, Feng T, Franceschini N, Tang H, Gao J, Sung YJ, the COGENT BP consortium, Elston RC, Williams SM, Cooper RS, Mu TW, Zhu XPLoS Genet
- Hearing Preservation Surgery for Cochlear Implantation: A Meta-analysis.Maria PL, Gluth MB, Yuan Y, Atlas MD, Henry Blevins NOtol Neurotol
- Physics, Emergence, and the Connectome.Laughlin RBNeuron
- Mania risk and creativity: A multi-method study of the role of motivation.Ruiter M, Johnson SLJ Affect Disord
- Vicinal Diamination of Alkenes under Rh-Catalysis.Olson DE, Su JY, Roberts DA, Du Bois JJ Am Chem Soc
- Methylation QTLs Are Associated with Coordinated Changes in Transcription Factor Binding, Histone Modifications, and Gene Expression Levels.Banovich NE, Lan X, McVicker G, van de Geijn B, Degner JF, Blischak JD, Roux J, Pritchard JK, Gilad YPLoS Genet
- Utility of Clinical Biomarkers to Predict Central Line Associated Bloodstream Infections After Congenital Heart Surgery.Shin AY, Jin B, Hao S, Hu Z, Sutherland S, McCammond A, Axelrod D, Sharek P, Roth SJ, Ling XBPediatr Infect Dis J
- Diagnosis and treatment of pediatric osteoporosis.Bachrach LKCurr Opin Endocrinol Diabetes Obes
- LprG-Mediated Surface Expression of Lipoarabinomannan Is Essential for Virulence of Mycobacterium tuberculosis.Gaur RL, Ren K, Blumenthal A, Bhamidi S, Gibbs S, Jackson M, Zare RN, Ehrt S, Ernst JD, Banaei NPLoS Pathog
- Lack of Impact of Mild Obstructive Sleep Apnea on Sleepiness, Mood and Quality of Life.Quan SF, Budhiraja R, Batool-Anwar S, Gottlieb DJ, Eichling P, Patel S, Shen W, Walsh JK, Kushida CASouthwest J Pulm Crit Care
- Durable Response to Crizotinib in a MET-Amplified, KRAS-Mutated Carcinoma of Unknown Primary.Palma NA, Ali SM, O'Connor J, Dutta D, Wang K, Soman S, Palmer GA, Morosini D, Ross JS, Lipson D, Stephens PJ, Patel M, Miller VA, Koutrelakos NCase Rep Oncol
- In vivo knockdown of Piccolino disrupts presynaptic ribbon morphology in mouse photoreceptor synapses.Regus-Leidig H, Fuchs M, Löhner M, Leist SR, Leal-Ortiz S, Chiodo VA, Hauswirth WW, Garner CC, Brandstätter JHFront Cell Neurosci
- Global malnutrition overlaps with pollinator-dependent micronutrient production.Chaplin-Kramer R, Dombeck E, Gerber J, Knuth KA, Mueller ND, Mueller M, Ziv G, Klein AMProc Biol Sci
- The role of migration in the evolution of phenotypic switching.Carja O, Furrow RE, Feldman MWProc Biol Sci
- Electrical stimulation of the left and right human fusiform gyrus causes different effects in conscious face perception.Rangarajan V, Hermes D, Foster BL, Weiner KS, Jacques C, Grill-Spector K, Parvizi JJ Neurosci
- Regulation of synaptic extracellular matrix composition is critical for proper synapse morphology.Kurshan PT, Phan AQ, Wang GJ, Crane MM, Lu H, Shen KJ Neurosci
- Registries Collecting Level-I through IV Data: Institutional and Multicenter Use: AAOS Exhibit Selection.Hansen VJ, Greene ME, Bragdon MA, Nebergall AK, Barr CJ, Huddleston JI, Bragdon CR, Malchau HJ Bone Joint Surg Am
- Structure and function of REP34 implicates carboxypeptidase activity in Francisella tularensis host-cell invasion.Feld GK, El-Etr S, Corzett MH, Hunter MS, Belhocine K, Monack DM, Frank M, Segelke BW, Rasley AJ Biol Chem
- Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.Perry JR, Day F, Elks CE, Sulem P, Thompson DJ, Ferreira T, He C, Chasman DI, Esko T, Thorleifsson G, Albrecht E, Ang WQ, Corre T, Cousminer DL, Feenstra B, Franceschini N, Ganna A, Johnson AD, Kjellqvist S, Lunetta KL, McMahon G, Nolte IM, Paternoster L, Porcu E, Smith AV, Stolk L, Teumer A, Tšernikova N, Tikkanen E, Ulivi S, Wagner EK, Amin N, Bierut LJ, Byrne EM, Hottenga JJ, Koller DL, Mangino M, Pers TH, Yerges-Armstrong LM, Hua Zhao J, Andrulis IL, Anton-Culver H, Atsma F, Bandinelli S, Beckmann MW, Benitez J, Blomqvist C, Bojesen SE, Bolla MK, Bonanni B, Brauch H, Brenner H, Buring JE, Chang-Claude J, Chanock S, Chen J, Chenevix-Trench G, Collée JM, Couch FJ, Couper D, Coviello AD, Cox A, Czene K, D'adamo AP, Davey Smith G, De Vivo I, Demerath EW, Dennis J, Devilee P, Dieffenbach AK, Dunning AM, Eiriksdottir G, Eriksson JG, Fasching PA, Ferrucci L, Flesch-Janys D, Flyger H, Foroud T, Franke L, Garcia ME, García-Closas M, Geller F, de Geus EE, Giles GG, Gudbjartsson DF, Gudnason V, Guénel P, Guo S, Hall P, Hamann U, Haring R, Hartman CA, Heath AC, Hofman A, Hooning MJ, Hopper JL, Hu FB, Hunter DJ, Karasik D, Kiel DP, Knight JA, Kosma VM, Kutalik Z, Lai S, Lambrechts D, Lindblom A, Mägi R, Magnusson PK, Mannermaa A, Martin NG, Masson G, McArdle PF, McArdle WL, Melbye M, Michailidou K, Mihailov E, Milani L, Milne RL, Nevanlinna H, Neven P, Nohr EA, Oldehinkel AJ, Oostra BA, Palotie A, Peacock M, Pedersen NL, Peterlongo P, Peto J, Pharoah PD, Postma DS, Pouta A, Pylkäs K, Radice P, Ring S, Rivadeneira F, Robino A, Rose LM, Rudolph A, Salomaa V, Sanna S, Schlessinger D, Schmidt MK, Southey MC, Sovio U, Stampfer MJ, Stöckl D, Storniolo AM, Timpson NJ, Tyrer J, Visser JA, Vollenweider P, Völzke H, Waeber G, Waldenberger M, Wallaschofski H, Wang Q, Willemsen G, Winqvist R, Wolffenbuttel BH, Wright MJ, Australian Ovarian Cancer Study, The GENICA Network, kConFab, The LifeLines Cohort Study, The InterAct Consortium, Early Growth Genetics (EGG) Consortium, Boomsma DI, Econs MJ, Khaw KT, Loos RJ, McCarthy MI, Montgomery GW, Rice JP, Streeten EA, Thorsteinsdottir U, van Duijn CM, Alizadeh BZ, Bergmann S, Boerwinkle E, Boyd HA, Crisponi L, Gasparini P, Gieger C, Harris TB, Ingelsson E, Järvelin MR, Kraft P, Lawlor D, Metspalu A, Pennell CE, Ridker PM, Snieder H, Sørensen TI, Spector TD, Strachan DP, Uitterlinden AG, Wareham NJ, Widen E, Zygmunt M, Murray A, Easton DF, Stefansson K, Murabito JM, Ong KKNature
- Vitamin D and experimental invasive aspergillosis.Sirivoranankul C, Martinez M, Chen V, Clemons KV, Stevens DAMed Mycol
- WholeCellSimDB: a hybrid relational/HDF database for whole-cell model predictions.Karr JR, Phillips NC, Covert MWDatabase (Oxford)
- Effects of Human Anti-Spike Protein Receptor Binding Domain Antibodies on SARS-Coronavirus Neutralization Escape and Fitness.Sui J, Deming M, Rockx B, Liddington RC, Zhu QK, Baric RS, Marasco WAJ Virol
- The Conserved Disulfide Bond within Domain II (D-II) of Epstein-Barr Virus (EBV) gH has Divergent Roles in Membrane Fusion with Epithelial Cells and B Cells.Möhl BS, Sathiyamoorthy K, Jardetzky TS, Longnecker RJ Virol
- The Impact of Accelerometer Use in Exercise-Associated Hypoglycemia Prevention in Type 1 Diabetes.Stenerson M, Cameron F, Payne SR, Payne SL, Ly TT, Wilson DM, Buckingham BAJ Diabetes Sci Technol
- Clinical and immunologic predictors of death after an acute opportunistic infection: results from ACTG A5164.Grant PM, Komarow L, Sanchez A, Sattler FR, Asmuth DM, Pollard RB, Zolopa ARHIV Clin Trials
- CT perfusion of the liver: principles and applications in oncology.Kim SH, Kamaya A, Willmann JKRadiology
- Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors.Rothwell PE, Fuccillo MV, Maxeiner S, Hayton SJ, Gokce O, Lim BK, Fowler SC, Malenka RC, Südhof TCCell
- Glucose regulates mitochondrial motility via Milton modification by O-GlcNAc transferase.Pekkurnaz G, Trinidad JC, Wang X, Kong D, Schwarz TLCell
- Prognostic importance of volumetric measurements in stage I lung adenocarcinoma.Yanagawa M, Tanaka Y, Leung AN, Morii E, Kusumoto M, Watanabe S, Watanabe H, Inoue M, Okumura M, Gyobu T, Ueda K, Honda O, Sumikawa H, Johkoh T, Tomiyama NRadiology
- Beyond the proteome: Mass Spectrometry Special Interest Group (MS-SIG) at ISMB/ECCB 2013.MS-SIG 2013 Organizers, Ryu SY, Payne SH, Schaab C, Xiao WBioinformatics
- Micropatterning microtubules.Portran DMethods Cell Biol
- Hormonal regulation of microRNA expression in steroid producing cells of the ovary, testis and adrenal gland.Hu Z, Shen WJ, Cortez Y, Tang X, Liu LF, Kraemer FB, Azhar SPLoS One
- Intraoperative hyperthermia during cesarean section: a pertinent lesson.Firago V, Brock-Utne JGInt J Obstet Anesth
- High rate of preterm birth in pregnancies complicated by rheumatoid arthritis.Langen ES, Chakravarty EF, Liaquat M, El-Sayed YY, Druzin MLAm J Perinatol
Fiber-Optic System for Dual-Modality Imaging of Glucose Probes 18F-FDG and 6-NBDG in Atherosclerotic Plaques.
PLoS One. 2014;9(9):e108108
Authors: Zaman RT, Kosuge H, Pratx G, Carpenter C, Xing L, McConnell MV
BACKGROUND: Atherosclerosis is a progressive inflammatory condition that underlies coronary artery disease (CAD)-the leading cause of death in the United States. Thus, the ultimate goal of this research is to advance our understanding of human CAD by improving the characterization of metabolically active vulnerable plaques within the coronary arteries using a novel catheter-based imaging system. The aims of this study include (1) developing a novel fiber-optic imaging system with a scintillator to detect both 18F and fluorescent glucose probes, and (2) validating the system on ex vivo murine plaques.
METHODS: A novel design implements a flexible fiber-optic catheter consisting of both a radio-luminescence and a fluorescence imaging system to detect radionuclide 18F-fluorodeoxyglucose (18F-FDG) and the fluorescent analog 6-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-6-Deoxyglucose (6-NBDG), respectively. Murine macrophage-rich atherosclerotic carotid plaques were imaged ex vivo after intravenous delivery of 18F-FDG or 6-NBDG. Confirmatory optical imaging by IVIS-200 and autoradiography were also performed.
RESULTS: Our fiber-optic imaging system successfully visualized both 18F-FDG and 6-NBDG probes in atherosclerotic plaques. For 18F-FDG, the ligated left carotid arteries (LCs) exhibited 4.9-fold higher radioluminescence signal intensity compared to the non-ligated right carotid arteries (RCs) (2.6×104±1.4×103 vs. 5.4×103±1.3×103 A.U., P = 0.008). Similarly, for 6-NBDG, the ligated LCs emitted 4.3-fold brighter fluorescent signals than the control RCs (1.6×102±2.7×101 vs. 3.8×101±5.9 A.U., P = 0.002). The higher uptake of both 18F-FDG and 6-NBDG in ligated LCs were confirmed with the IVIS-200 system. Autoradiography further verified the higher uptake of 18F-FDG by the LCs.
CONCLUSIONS: This novel fiber-optic imaging system was sensitive to both radionuclide and fluorescent glucose probes taken up by murine atherosclerotic plaques. In addition, 6-NBDG is a promising novel fluorescent probe for detecting macrophage-rich atherosclerotic plaques.
PMID: 25233472 [PubMed - as supplied by publisher]
A Universal Approach to Prepare Reagents for DNA-Assisted Protein Analysis.
PLoS One. 2014;9(9):e108061
Authors: Yan J, Gu GJ, Jost C, Hammond M, Plückthun A, Landegren U, Kamali-Moghaddam M
The quality of DNA-labeled affinity probes is critical in DNA-assisted protein analyses, such as proximity ligation and extension assays, immuno-PCR, and immuno-rolling circle amplification reactions. Efficient, high-performance methods are therefore required for isolation of pure conjugates from reactions where DNA strands have been coupled to antibodies or recombinant affinity reagents. Here we describe a universal, scalable approach for preparing high-quality oligonucleotide-protein conjugates by sequentially removing any unconjugated affinity reagents and remaining free oligonucleotides from conjugation reactions. We applied the approach to generate high-quality probes using either antibodies or recombinant affinity reagents. The purified high-grade probes were used in proximity ligation assays in solution and in situ, demonstrating both augmented assay sensitivity and improved signal-to-noise ratios.
PMID: 25233463 [PubMed - as supplied by publisher]
The Association of the Vanin-1 N131S Variant with Blood Pressure Is Mediated by Endoplasmic Reticulum-Associated Degradation and Loss of Function.
PLoS Genet. 2014 Sep;10(9):e1004641
Authors: Wang YJ, Tayo BO, Bandyopadhyay A, Wang H, Feng T, Franceschini N, Tang H, Gao J, Sung YJ, the COGENT BP consortium, Elston RC, Williams SM, Cooper RS, Mu TW, Zhu X
High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)-rs2272996-in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT) of African Americans (P = 0.01). This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 protein levels. We observed that the N131S vanin-1 is subjected to rapid endoplasmic reticulum-associated degradation (ERAD) as the underlying mechanism for its reduction. Using HEK293 cells stably expressing vanin-1 variants, we showed that N131S vanin-1 was degraded significantly faster than wild type (WT) vanin-1. Consequently, there were only minimal quantities of variant vanin-1 present on the plasma membrane and greatly reduced pantetheinase activity. Application of MG-132, a proteasome inhibitor, resulted in accumulation of ubiquitinated variant protein. A further experiment demonstrated that atenolol and diltiazem, two current drugs for treating hypertension, reduce the vanin-1 protein level. Our study provides strong biological evidence for the association of the identified SNP with BP and suggests that vanin-1 misfolding and degradation are the underlying molecular mechanism.
PMID: 25233454 [PubMed - as supplied by publisher]
Hearing Preservation Surgery for Cochlear Implantation: A Meta-analysis.
Otol Neurotol. 2014 Sep 17;
Authors: Maria PL, Gluth MB, Yuan Y, Atlas MD, Henry Blevins N
OBJECTIVE: To examine the results of hearing preservation in cochlear implantation surgery to identify surgical technical factors, electrode array design factors, and steroid usage, which predicts greater low-frequency hearing preservation.
DATA SOURCES: A thorough search of Medline and Pubmed of English studies from January 1, 1995, to January 1, 2013, was performed using the key words "electric and acoustic hearing" or "hybrid cochlear implant" or "EAS cochlear implant" or "partial deafness cochlear implant" or "bimodal hearing cochlear implant" or "hearing preservation cochlear implant."
STUDY SELECTION: The meta-analysis was conducted according to the PRISMA statement. Only articles in English were included. Studies were included if hearing preservation was the primary end point. A final number of 24 studies met the inclusion criteria.
DATA EXTRACTION: Patient populations were analyzed as intention to treat. Data were extracted from raw audiograms where possible. Data were excluded if not all explanatory variables were present or if variable values were ambiguous.
DATA SYNTHESIS: The weighted least-squares regression method was used to determine the predictive power of each explanatory variable across all studies.
CONCLUSION: In this meta-analysis, the following are associated with better hearing preservation: cochleostomy over the round window approach, posterior tympanotomy over the suprameatal approach, a slow electrode array insertion technique over insertion of less than 30 seconds, a soft tissue cochleostomy seal over a fibrin glue only seal and the use of postoperative systemic steroids. Longer electrode arrays, topical steroid use, and lubricant use for electrode array insertion did not give an advantage.
PMID: 25233333 [PubMed - as supplied by publisher]
Physics, Emergence, and the Connectome.
Neuron. 2014 Sep 17;83(6):1253-1255
Authors: Laughlin RB
Experience with complex systems more primitive than the brain teaches important lessons about big data in biology. Chief among them is that physical laws, relationships among measured things that are always true, emerge out of chaos, not the other way around. Correct prediction (as opposed to incorrect prediction) from large data sets requires understanding of these laws. The reason is that the same processes that make them also make the system wildly error-intolerant if the errors are too large. This instability routinely causes computer simulations of even primitive systems to fail by enabling mistakes to cascade into ever worsening falsehoods. The more complex and sophisticated the system is, the more intolerant to errors it becomes.
PMID: 25233307 [PubMed - as supplied by publisher]
Mania risk and creativity: A multi-method study of the role of motivation.
J Affect Disord. 2014 Sep 3;170C:52-58
Authors: Ruiter M, Johnson SL
BACKGROUND: Substantial literature has linked bipolar disorder and risk for bipolar disorder with creative accomplishment, but few multimodal studies of creativity are available, and little is known about mechanisms.
METHODS: We use a multi-method approach to test the association of bipolar risk with several creativity measures, including creative accomplishments, creative personality traits, and a laboratory index of insight. We also examined whether multiple facets of motivation accounted for the links of bipolar risk with creativity. Among 297 undergraduates, mania risk, as measured with the Hypomanic Personality Scale was related to lifetime creativity and creative personality, but not to performance on the insight task. Motivational traits appeared to mediate the links of mania risk with both lifetime creative accomplishments and self-rated creativity.
LIMITATIONS: The study relied on a cross-sectional design and a convenience sample.
CONCLUSIONS: Future studies would benefit from exploring motivation as a positive aspect of manic vulnerability that may foster greater creativity.
PMID: 25233239 [PubMed - as supplied by publisher]
Vicinal Diamination of Alkenes under Rh-Catalysis.
J Am Chem Soc. 2014 Sep 18;
Authors: Olson DE, Su JY, Roberts DA, Du Bois J
The synthesis of 1,2-diamines has been achieved through a single-step, tandem sequence involving Rh-catalyzed aziridination followed by NaI-promoted rearrangement to an isomeric cyclic sulfamide. Facile ring opening of these products in hot water and pyridine affords differentially protected vicinal diamines. Demonstration of the utility of this method for the syntheses of (±)-enduracididine and (±)-allo-enduracididine is highlighted.
PMID: 25233140 [PubMed - as supplied by publisher]
Methylation QTLs Are Associated with Coordinated Changes in Transcription Factor Binding, Histone Modifications, and Gene Expression Levels.
PLoS Genet. 2014 Sep;10(9):e1004663
Authors: Banovich NE, Lan X, McVicker G, van de Geijn B, Degner JF, Blischak JD, Roux J, Pritchard JK, Gilad Y
DNA methylation is an important epigenetic regulator of gene expression. Recent studies have revealed widespread associations between genetic variation and methylation levels. However, the mechanistic links between genetic variation and methylation remain unclear. To begin addressing this gap, we collected methylation data at ∼300,000 loci in lymphoblastoid cell lines (LCLs) from 64 HapMap Yoruba individuals, and genome-wide bisulfite sequence data in ten of these individuals. We identified (at an FDR of 10%) 13,915 cis methylation QTLs (meQTLs)-i.e., CpG sites in which changes in DNA methylation are associated with genetic variation at proximal loci. We found that meQTLs are frequently associated with changes in methylation at multiple CpGs across regions of up to 3 kb. Interestingly, meQTLs are also frequently associated with variation in other properties of gene regulation, including histone modifications, DNase I accessibility, chromatin accessibility, and expression levels of nearby genes. These observations suggest that genetic variants may lead to coordinated molecular changes in all of these regulatory phenotypes. One plausible driver of coordinated changes in different regulatory mechanisms is variation in transcription factor (TF) binding. Indeed, we found that SNPs that change predicted TF binding affinities are significantly enriched for associations with DNA methylation at nearby CpGs.
PMID: 25233095 [PubMed - as supplied by publisher]
Utility of Clinical Biomarkers to Predict Central Line Associated Bloodstream Infections After Congenital Heart Surgery.
Pediatr Infect Dis J. 2014 Sep 17;
Authors: Shin AY, Jin B, Hao S, Hu Z, Sutherland S, McCammond A, Axelrod D, Sharek P, Roth SJ, Ling XB
BACKGROUND:: Central line associated bloodstream infections is an important contributor of morbidity and mortality in children recovering from congenital heart surgery. The reliability of commonly used biomarkers to differentiate these patients have not been specifically studied.
METHODS:: This was a retrospective cohort study in a university-affiliated children's hospital examining all patients with congenital or acquired heart disease admitted to the cardiovascular intensive care unit following cardiac surgery who underwent evaluation for a catheter-associated bloodstream infection.
RESULTS:: Among 1260 cardiac surgeries performed, 451 encounters underwent an infection evaluation post-operatively. Twenty-five instances of CLABSI and 227 instances of a negative infection evaluation were the subject of analysis. Patients with CLABSI tended to be younger (1.34 vs 4.56 years, p = 0.011) and underwent more complex surgery (RACHS-1 score 3.79 vs 3.04, p = 0.039). The two groups were indistinguishable in WBC, PMNs and band count at the time of their presentation. On multivariate analysis, CLABSI was associated with fever (adjusted OR 4.78; 95% CI, 1.6 to 5.8) and elevated CRP (adjusted OR 1.28; 95% CI, 1.09 to 1.68) after adjusting for differences between the two groups. Receiver operating characteristic analysis demonstrated the discriminatory power of both fever and CRP (area under curve 0.7247, 95% CI, 0.42 to 0.74 and 0.58, 95% CI 0.4208 to 0.7408). We calculated multilevel likelihood ratios for a spectrum of temperature and CRP values.
CONCLUSIONS:: We found commonly used serum biomarkers such as fever and CRP not to be helpful discriminators in patients following congenital heart surgery.
PMID: 25232780 [PubMed - as supplied by publisher]
Diagnosis and treatment of pediatric osteoporosis.
Curr Opin Endocrinol Diabetes Obes. 2014 Sep 17;
Authors: Bachrach LK
PURPOSE OF REVIEW: Progress toward identifying and treating disorders of bone fragility in pediatric patients has been considerable in recent years. This article will summarize several key advances in the management of osteoporosis in children and adolescents.
RECENT FINDINGS: Recommendations from the 2013 pediatric Position Development Conference provide expert guidance for evaluating bone health in younger patients. The diagnosis of pediatric osteoporosis can be made in a child with low-trauma vertebral fractures or a combination of low bone mass and long bone fractures. Management of bone fragility includes optimizing nutrition, activity, and treatment of the underlying disease. Pharmacologic agents can be considered if these measures fail to prevent further bone loss or fractures. Although the efficacy and safety of several intravenous and oral bisphosphonates have been examined, there is still no consensus on the optimal drug, dose, or duration of treatment. Observational studies of children with secondary osteoporosis provide insight into risk factors for fracture or the potential for recovery.
SUMMARY: Despite advances in the diagnosis and treatment of pediatric osteoporosis, more research is needed. Randomized controlled trials of pharmacologic agents should be defined to target those identified at the highest risk by observational studies. VIDEO ABSTRACT::
PMID: 25232753 [PubMed - as supplied by publisher]
LprG-Mediated Surface Expression of Lipoarabinomannan Is Essential for Virulence of Mycobacterium tuberculosis.
PLoS Pathog. 2014 Sep;10(9):e1004376
Authors: Gaur RL, Ren K, Blumenthal A, Bhamidi S, Gibbs S, Jackson M, Zare RN, Ehrt S, Ernst JD, Banaei N
Mycobacterium tuberculosis employs various virulence strategies to subvert host immune responses in order to persist and cause disease. Interaction of M. tuberculosis with mannose receptor on macrophages via surface-exposed lipoarabinomannan (LAM) is believed to be critical for cell entry, inhibition of phagosome-lysosome fusion, and intracellular survival, but in vivo evidence is lacking. LprG, a cell envelope lipoprotein that is essential for virulence of M. tuberculosis, has been shown to bind to the acyl groups of lipoglycans but the role of LprG in LAM biosynthesis and localization remains unknown. Using an M. tuberculosis lprG mutant, we show that LprG is essential for normal surface expression of LAM and virulence of M. tuberculosis attributed to LAM. The lprG mutant had a normal quantity of LAM in the cell envelope, but its surface was altered and showed reduced expression of surface-exposed LAM. Functionally, the lprG mutant was defective for macrophage entry and inhibition of phagosome-lysosome fusion, was attenuated in macrophages, and was killed in the mouse lung with the onset of adaptive immunity. This study identifies the role of LprG in surface-exposed LAM expression and provides in vivo evidence for the essential role surface LAM plays in M. tuberculosis virulence. Findings have translational implications for therapy and vaccine development.
PMID: 25232742 [PubMed - as supplied by publisher]
Lack of Impact of Mild Obstructive Sleep Apnea on Sleepiness, Mood and Quality of Life.
Southwest J Pulm Crit Care. 2014;9(1):44-56
Authors: Quan SF, Budhiraja R, Batool-Anwar S, Gottlieb DJ, Eichling P, Patel S, Shen W, Walsh JK, Kushida CA
BACKGROUND AND OBJECTIVES: Obstructive sleep apnea (OSA) is associated with sleepiness, depression and reduced quality of life. However, it is unclear whether mild OSA has these negative impacts. Using data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES), this study determined whether participants with mild OSA had greater sleepiness, more depressive symptoms and poorer quality of life in comparison to those without OSA.
METHODS: 239 individuals evaluated for participation in APPLES with a baseline apnea hypopnea index (AHI) < 15 /hour were assigned to 1 of 2 groups: No OSA (N=40, AHI < 5 /hour) or Mild OSA (N=199, 5 to <15 /hour) based on their screening polysomnogram. Scores on their Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale (SSS), Hamilton Rating Scale for Depression (HAM-D), Profile of Mood States (POMS) and Sleep Apnea Quality of Life Index (SAQLI) were compared between groups.
RESULTS: There were no significant differences between the No OSA and Mild OSA groups on any of the 5 measures: ESS (No OSA, 9.8 ± 3.5 vs Mild OSA, 10.6 ± 4.3, p=0.26), SSS,(2.8 ± 0.9 vs. 2.9 ± 1.0, p=0.52), HAM-D (4.6 ± 3.0 vs. 4.9 ± 4.7, p=0.27), POMS (33.5 ± 22.3 vs. 28.7 ± 22.0, p=0.70), SAQLI (4.5 ± 0.8 vs. 4.7 ± 0.7, p=0.39).
CONCLUSION: Individuals with mild OSA in this cohort do not have worse sleepiness, mood or quality of life in comparison to those without OSA.
PMID: 25232509 [PubMed - as supplied by publisher]
Durable Response to Crizotinib in a MET-Amplified, KRAS-Mutated Carcinoma of Unknown Primary.
Case Rep Oncol. 2014 May;7(2):503-8
Authors: Palma NA, Ali SM, O'Connor J, Dutta D, Wang K, Soman S, Palmer GA, Morosini D, Ross JS, Lipson D, Stephens PJ, Patel M, Miller VA, Koutrelakos N
BACKGROUND: Carcinoma of unknown primary (CUP) accounts for 3-5% of all adult solid tumors. An extensive search for the anatomic site of origin is often undertaken in an attempt to tailor systemic treatment, but the latter often has limited efficacy - especially in the setting of an initial treatment failure. Molecularly targeted therapy is an emerging approach that may offer greater efficacy and less toxicity but is most likely to be effective when pairing a tumor harboring a sensitizing genomic alteration with an agent directed at the altered gene product. We report a patient with a CUP harboring a MET amplification with a complete metabolic response to crizotinib despite also harboring a KRAS mutation.
METHODS: Ge-nomic profiling was performed using a clinical next-generation-sequencing-based assay, FoundationOne(®), in a CAP-accredited laboratory certified by Clinical Laboratory Improvement Amendments (Foundation Medicine, Cambridge, Mass., USA).
RESULTS: The CUP harbored both MET amplification (16 copies) and a KRAS G12V mutation. The patient was treated with crizotinib, a MET inhibitor, and has experienced a complete normalization of tumor metabolic activity for more than 19 months.
CONCLUSIONS: Genomic profiling of CUP may reveal clinically meaningful genomic alterations that can guide targeted therapy decision-making. The use of this approach should be studied prospectively as a strategy for the effective treatment of CUP patients and for avoiding resource-intensive workups to identify the tumor site of origin.
PMID: 25232318 [PubMed]
In vivo knockdown of Piccolino disrupts presynaptic ribbon morphology in mouse photoreceptor synapses.
Front Cell Neurosci. 2014;8:259
Authors: Regus-Leidig H, Fuchs M, Löhner M, Leist SR, Leal-Ortiz S, Chiodo VA, Hauswirth WW, Garner CC, Brandstätter JH
Piccolo is the largest known cytomatrix protein at active zones of chemical synapses. A growing number of studies on conventional chemical synapses assign Piccolo a role in the recruitment and integration of molecules relevant for both endo- and exocytosis of synaptic vesicles, the dynamic assembly of presynaptic F-actin, as well as the proteostasis of presynaptic proteins, yet a direct function in the structural organization of the active zone has not been uncovered in part due to the expression of multiple alternatively spliced isoforms. We recently identified Piccolino, a Piccolo splice variant specifically expressed in sensory ribbon synapses of the eye and ear. Here we down regulated Piccolino in vivo via an adeno-associated virus-based RNA interference approach and explored the impact on the presynaptic structure of mouse photoreceptor ribbon synapses. Detailed immunocytochemical light and electron microscopical analysis of Piccolino knockdown in photoreceptors revealed a hitherto undescribed photoreceptor ribbon synaptic phenotype with striking morphological changes of synaptic ribbon ultrastructure.
PMID: 25232303 [PubMed]
Global malnutrition overlaps with pollinator-dependent micronutrient production.
Proc Biol Sci. 2014 Nov 7;281(1794)
Authors: Chaplin-Kramer R, Dombeck E, Gerber J, Knuth KA, Mueller ND, Mueller M, Ziv G, Klein AM
Pollinators contribute around 10% of the economic value of crop production globally, but the contribution of these pollinators to human nutrition is potentially much higher. Crops vary in the degree to which they benefit from pollinators, and many of the most pollinator-dependent crops are also among the richest in micronutrients essential to human health. This study examines regional differences in the pollinator dependence of crop micronutrient content and reveals overlaps between this dependency and the severity of micronutrient deficiency in people around the world. As much as 50% of the production of plant-derived sources of vitamin A requires pollination throughout much of Southeast Asia, whereas other essential micronutrients such as iron and folate have lower dependencies, scattered throughout Africa, Asia and Central America. Micronutrient deficiencies are three times as likely to occur in areas of highest pollination dependence for vitamin A and iron, suggesting that disruptions in pollination could have serious implications for the accessibility of micronutrients for public health. These regions of high nutritional vulnerability are understudied in the pollination literature, and should be priority areas for research related to ecosystem services and human well-being.
PMID: 25232140 [PubMed - in process]
The role of migration in the evolution of phenotypic switching.
Proc Biol Sci. 2014 Nov 7;281(1794)
Authors: Carja O, Furrow RE, Feldman MW
Stochastic switching is an example of phenotypic bet hedging, where an individual can switch between different phenotypic states in a fluctuating environment. Although the evolution of stochastic switching has been studied when the environment varies temporally, there has been little theoretical work on the evolution of phenotypic switching under both spatially and temporally fluctuating selection pressures. Here, we explore the interaction of temporal and spatial change in determining the evolutionary dynamics of phenotypic switching. We find that spatial variation in selection is important; when selection pressures are similar across space, migration can decrease the rate of switching, but when selection pressures differ spatially, increasing migration between demes can facilitate the evolution of higher rates of switching. These results may help explain the diverse array of non-genetic contributions to phenotypic variability and phenotypic inheritance observed in both wild and experimental populations.
PMID: 25232136 [PubMed - in process]
Electrical stimulation of the left and right human fusiform gyrus causes different effects in conscious face perception.
J Neurosci. 2014 Sep 17;34(38):12828-36
Authors: Rangarajan V, Hermes D, Foster BL, Weiner KS, Jacques C, Grill-Spector K, Parvizi J
Neuroimaging and electrophysiological studies across species have confirmed bilateral face-selective responses in the ventral temporal cortex (VTC) and prosopagnosia is reported in patients with lesions in the VTC including the fusiform gyrus (FG). As imaging and electrophysiological studies provide correlative evidence, and brain lesions often comprise both white and gray matter structures beyond the FG, we designed the current study to explore the link between face-related electrophysiological responses in the FG and the causal effects of electrical stimulation of the left or right FG in face perception. We used a combination of electrocorticography (ECoG) and electrical brain stimulation (EBS) in 10 human subjects implanted with intracranial electrodes in either the left (5 participants, 30 FG sites) or right (5 participants, 26 FG sites) hemispheres. We identified FG sites with face-selective ECoG responses, and recorded perceptual reports during EBS of these sites. In line with existing literature, face-selective ECoG responses were present in both left and right FG sites. However, when the same sites were stimulated, we observed a striking difference between hemispheres. Only EBS of the right FG caused changes in the conscious perception of faces, whereas EBS of strongly face-selective regions in the left FG produced non-face-related visual changes, such as phosphenes. This study examines the relationship between correlative versus causal nature of ECoG and EBS, respectively, and provides important insight into the differential roles of the right versus left FG in conscious face perception.
PMID: 25232118 [PubMed - in process]
Regulation of synaptic extracellular matrix composition is critical for proper synapse morphology.
J Neurosci. 2014 Sep 17;34(38):12678-89
Authors: Kurshan PT, Phan AQ, Wang GJ, Crane MM, Lu H, Shen K
Synapses are surrounded by a layer of extracellular matrix (ECM), which is instrumental for their development and maintenance. ECM composition is dynamically controlled by proteases, but how the precise composition of the ECM affects synaptic morphology is largely unknown. Through an unbiased forward genetic screen, we found that Caenorhabditis elegans gon-1, a conserved extracellular ADAMTS protease, is required for maintaining proper synaptic morphology at the neuromuscular junction. In gon-1 mutants, once synapse formation is complete, motor neuron presynaptic varicosities develop into large bulbous protrusions that contain synaptic vesicles and active zone proteins. A concomitant overgrowth of postsynaptic muscle membrane is found in close apposition to presynaptic axonal protrusions. Mutations in the muscle-specific, actin-severing protein cofilin (unc-60) suppress the axon phenotype, suggesting that muscle outgrowth is necessary for presynaptic protrusions. gon-1 mutants can also be suppressed by loss of the ECM components collagen IV (EMB-9) and fibulin (FBL-1). We propose that GON-1 regulates a developmental switch out of an initial "pro-growth" phase during which muscle arms grow out and form synapses with motor neuron axons. We postulate that this switch involves degradation or reorganization of collagen IV (EMB-9), whereas FBL-1 opposes GON-1 by stabilizing EMB-9. Our results describe a mechanism for regulating synaptic ECM composition and reveal the importance of precise ECM composition for neuronal morphology and synapse integrity.
PMID: 25232106 [PubMed - in process]
Registries Collecting Level-I through IV Data: Institutional and Multicenter Use: AAOS Exhibit Selection.
J Bone Joint Surg Am. 2014 Sep 17;96(18):e160
Authors: Hansen VJ, Greene ME, Bragdon MA, Nebergall AK, Barr CJ, Huddleston JI, Bragdon CR, Malchau H
PMID: 25232090 [PubMed - in process]
Structure and function of REP34 implicates carboxypeptidase activity in Francisella tularensis host-cell invasion.
J Biol Chem. 2014 Sep 17;
Authors: Feld GK, El-Etr S, Corzett MH, Hunter MS, Belhocine K, Monack DM, Frank M, Segelke BW, Rasley A
Francisella tularensis is the etiological agent of tularemia, or rabbit fever. While F. tularensis is a recognized biothreat agent with broad and expanding geographical range, its mechanism of infection and environmental persistence remain poorly understood. Previously, we identified seven F. tularensis proteins that induce a rapid encystment phenotype (REP) in the free-living amoeba, Acanthamoeba castellanii. Encystment is essential to the pathogen's long-term intracellular survival in amoeba. Here, we characterize the cellular and molecular function of REP34, a REP protein of mass 34 kDa. A REP34 knockout strain of F. tularensis has a reduced ability to both induce encystment in A. castellanii and invade human macrophages. We determined the crystal structure of REP34 to 2.05-A resolution and demonstrate robust carboxypeptidase B-like activity for the enzyme. REP34 is a zinc-containing monomeric protein with close structural homology to the metallocarboxypeptidase family of peptidases. REP34 possesses a novel topology and substrate binding pocket that deviates from the canonical funnelin structure of carboxypeptidases, putatively resulting in a catalytic role for a conserved tyrosine and distinct S1' recognition site. Taken together, these results identify REP34 as an active carboxypeptidase, implicate the enzyme as a potential key F. tularensis effector protein, and may help elucidate a mechanistic understanding of F. tularensis infection of phagocytic cells.
PMID: 25231992 [PubMed - as supplied by publisher]
Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
Nature. 2014 Jul 23;
Authors: Perry JR, Day F, Elks CE, Sulem P, Thompson DJ, Ferreira T, He C, Chasman DI, Esko T, Thorleifsson G, Albrecht E, Ang WQ, Corre T, Cousminer DL, Feenstra B, Franceschini N, Ganna A, Johnson AD, Kjellqvist S, Lunetta KL, McMahon G, Nolte IM, Paternoster L, Porcu E, Smith AV, Stolk L, Teumer A, Tšernikova N, Tikkanen E, Ulivi S, Wagner EK, Amin N, Bierut LJ, Byrne EM, Hottenga JJ, Koller DL, Mangino M, Pers TH, Yerges-Armstrong LM, Hua Zhao J, Andrulis IL, Anton-Culver H, Atsma F, Bandinelli S, Beckmann MW, Benitez J, Blomqvist C, Bojesen SE, Bolla MK, Bonanni B, Brauch H, Brenner H, Buring JE, Chang-Claude J, Chanock S, Chen J, Chenevix-Trench G, Collée JM, Couch FJ, Couper D, Coviello AD, Cox A, Czene K, D'adamo AP, Davey Smith G, De Vivo I, Demerath EW, Dennis J, Devilee P, Dieffenbach AK, Dunning AM, Eiriksdottir G, Eriksson JG, Fasching PA, Ferrucci L, Flesch-Janys D, Flyger H, Foroud T, Franke L, Garcia ME, García-Closas M, Geller F, de Geus EE, Giles GG, Gudbjartsson DF, Gudnason V, Guénel P, Guo S, Hall P, Hamann U, Haring R, Hartman CA, Heath AC, Hofman A, Hooning MJ, Hopper JL, Hu FB, Hunter DJ, Karasik D, Kiel DP, Knight JA, Kosma VM, Kutalik Z, Lai S, Lambrechts D, Lindblom A, Mägi R, Magnusson PK, Mannermaa A, Martin NG, Masson G, McArdle PF, McArdle WL, Melbye M, Michailidou K, Mihailov E, Milani L, Milne RL, Nevanlinna H, Neven P, Nohr EA, Oldehinkel AJ, Oostra BA, Palotie A, Peacock M, Pedersen NL, Peterlongo P, Peto J, Pharoah PD, Postma DS, Pouta A, Pylkäs K, Radice P, Ring S, Rivadeneira F, Robino A, Rose LM, Rudolph A, Salomaa V, Sanna S, Schlessinger D, Schmidt MK, Southey MC, Sovio U, Stampfer MJ, Stöckl D, Storniolo AM, Timpson NJ, Tyrer J, Visser JA, Vollenweider P, Völzke H, Waeber G, Waldenberger M, Wallaschofski H, Wang Q, Willemsen G, Winqvist R, Wolffenbuttel BH, Wright MJ, Australian Ovarian Cancer Study, The GENICA Network, kConFab, The LifeLines Cohort Study, The InterAct Consortium, Early Growth Genetics (EGG) Consortium, Boomsma DI, Econs MJ, Khaw KT, Loos RJ, McCarthy MI, Montgomery GW, Rice JP, Streeten EA, Thorsteinsdottir U, van Duijn CM, Alizadeh BZ, Bergmann S, Boerwinkle E, Boyd HA, Crisponi L, Gasparini P, Gieger C, Harris TB, Ingelsson E, Järvelin MR, Kraft P, Lawlor D, Metspalu A, Pennell CE, Ridker PM, Snieder H, Sørensen TI, Spector TD, Strachan DP, Uitterlinden AG, Wareham NJ, Widen E, Zygmunt M, Murray A, Easton DF, Stefansson K, Murabito JM, Ong KK
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
PMID: 25231870 [PubMed - as supplied by publisher]
Vitamin D and experimental invasive aspergillosis.
Med Mycol. 2014 Sep 17;
Authors: Sirivoranankul C, Martinez M, Chen V, Clemons KV, Stevens DA
Immune cells express the vitamin D receptor and vitamin D metabolizing enzymes. Favorable vitamin D effects have been indicated in tuberculosis. Vitamin D deficiency increases T helper (Th) 2 responses to Aspergillus, and it suppresses Th2 responses in cystic fibrosis-allergic bronchopulmonary aspergillosis. Can vitamin D modulate the proinflammatory effects of amphotericin B (AmB) therapy in aspergillosis? Groups of mice were infected intravenously (IV) with 3-8 × 10(6) Aspergillus fumigatus conidia. In six experiments, doses of 0.08, 2, or 4 μg/kg calcitriol (active form of vitamin D) were given intraperitoneally +/- AmB-deoxycholate (AmBd) at 0.4, 0.8, 1.2, 1.8, 3.3, or 4.5 mg/kg or 0.8 or 1.2 mg/kg IV. Calcitriol doses were selected to range from doses used in humans to those just below doses shown to decalcify murine bones. In most experiments, doses of calcitriol and AmBd (or control diluents) were given five times, on alternate days, to minimize drug-drug interactions. Calcitriol treatment began on the day of challenge, and survival assessed for 10 days. In no experiments did calcitriol alone significantly worsen or enhance survival or affect residual infection in survivors. Calcitriol also did not affect the efficacy of AmBd. In a representative experiment, AmBd at 0.8 or 1.2 mg/kg IV alone +/- calcitriol at 2 μg/kg enhanced survival (P ≤ 0.01). However, the AmBd regimens with calcitriol were not different than those without, and calcitriol alone was identical to controls. In disseminated invasive aspergillosis, calcitriol did not affect outcome nor influence antifungal efficacy.
PMID: 25231772 [PubMed - as supplied by publisher]
WholeCellSimDB: a hybrid relational/HDF database for whole-cell model predictions.
Database (Oxford). 2014;2014
Authors: Karr JR, Phillips NC, Covert MW
PMID: 25231498 [PubMed - in process]
Effects of Human Anti-Spike Protein Receptor Binding Domain Antibodies on SARS-Coronavirus Neutralization Escape and Fitness.
J Virol. 2014 Sep 17;
Authors: Sui J, Deming M, Rockx B, Liddington RC, Zhu QK, Baric RS, Marasco WA
The receptor binding domain (RBD) of the spike (S) glycoprotein of SARS-CoV is a major target of protective immunity in vivo. Although a large number of neutralizing antibodies (nAbs) have been developed, it remains unclear if a single RBD-targeting nAb or two in combination can prevent neutralization escape and if not, attenuate viral virulence in vivo. In this study, we used a large panel of human nAbs against an epitope which overlaps the interface between the RBD and its receptor, ACE2, to assess their cross-neutralization activities against a panel of human and zoonotic SARS-CoVs and neutralization escape mutants. We also investigated the neutralization escape profiles of these nAbs, and evaluated their effects on receptor binding and virus fitness in vitro and in mice. We found that some nAbs had great potency and breadth in neutralizing multiple viral stains including neutralization escape viruses derived from other nAbs, however no single nAb nor a combination of two blocked neutralization escape. Interestingly, in mice the neutralization escape mutant viruses showed either attenuation (Urbani-background) or increased virulence (GD03-background) consistent with the different binding affinities between their RBDs and the mouse ACE2. We conclude that using either single or dual nAb combinations to target a SARS-CoV RBD epitope that shows plasticity may have limitations for preventing neutralization escape during in vivo immunotherapy. However, RBD-directed nAbs may be useful for providing broad neutralization and prevention of escape variants when combined with other nAbs that target a second conserved epitope with less plasticity and more structural constraint.
IMPORTANCE: The emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) in 2002 and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in 2012 have resulted in severe human respiratory disease with high death rates. Their zoonotic origins highlight the likelihood of reemergence or further evolution into novel human coronavirus pathogens. Broadly neutralizing antibodies (nAbs) that prevent infection of related viruses represent an important immuno-strategy for combating coronaviruses infections, however for this strategy to succeed, it is essential to uncover nAb-mediated escape pathways and to pioneer strategies that prevent escape. Here, we used SARS-CoV as a research model and examined the escaping pathways of broadly nAbs that target the receptor binding domain (RBD) of the virus. We found that neither single nor two nAbs in combination blocked escape. Our results suggest that targeting conserved regions with less plasticity and more structural constraint rather than SARS-CoV RBD-like region(s) should have broader utility for antibody-based immunotherapy.
PMID: 25231316 [PubMed - as supplied by publisher]
The Conserved Disulfide Bond within Domain II (D-II) of Epstein-Barr Virus (EBV) gH has Divergent Roles in Membrane Fusion with Epithelial Cells and B Cells.
J Virol. 2014 Sep 17;
Authors: Möhl BS, Sathiyamoorthy K, Jardetzky TS, Longnecker R
Epstein-Barr virus (EBV) infects target cells via fusion with cellular membranes. For entry into epithelial cells, EBV requires the herpesvirus conserved core fusion machinery composed of glycoprotein B (gB) and gH/gL. In contrast, for B cell fusion it requires gB and gH/gL with gp42 serving as a cell tropism switch. The available crystal structures for gH/gL allow the targeted analysis of structural determinants of gH to identify functional regions critical for membrane fusion. Domain II of EBV gH contains two disulfide bonds (DB), the first is unique for EBV and closely related γ-herpesviruses. The second is conserved across the β- and γ-herpesviruses and is positioned to stabilize a putative syntaxin-like bundle motif. To analyze the role of these DBs in membrane fusion, gH was mutated by amino acid substitution of the DB cysteines. Mutation of the EBV-specific DB resulted in diminished gH/gL cell surface expression that correlated with diminished B cell and epithelial cell fusion. In contrast, mutation of the conserved DB resulted in wild-type-like B cell fusion whereas epithelial cell fusion was greatly reduced. The gH mutants bound well to gp42 but had diminished binding to epithelial cells. Tyrosine 336, located adjacent to cysteine 335 of the conserved DB, was also found to be important for DB stabilization and gH/gL function. We conclude that the conserved DB has a cell type specific function, since it is important for the binding of gH to epithelial cells initiating epithelial cell fusion but not for fusion with B cells and gp42 binding.
IMPORTANCE: EBV predominantly infects epithelial and B cells in humans, which can result in EBV-associated cancers such as Burkitt and Hodgkin lymphoma as well as nasopharyngeal carcinoma. EBV is also associated with a variety of lymphoproliferative disorders, typically of B cell origin, observed in immunosuppressed individuals such as post-transplant or HIV/AIDS patients. The gH/gL complex plays an essential but still poorly characterized role as an important determinant for EBV cell tropism. In our current studies, we found that mutants in the DB C278/C335 and a neighboring tyrosine 336 have cell type specific functional deficits with selective decreases in epithelial cell, but not B cell, binding and fusion. The present study brings new insights into the gH function as determinant for epithelial cell tropism during herpesvirus induced membrane fusion and highlights a specific gH motif required for epithelial cell fusion.
PMID: 25231307 [PubMed - as supplied by publisher]
The Impact of Accelerometer Use in Exercise-Associated Hypoglycemia Prevention in Type 1 Diabetes.
J Diabetes Sci Technol. 2014 Sep 17;
Authors: Stenerson M, Cameron F, Payne SR, Payne SL, Ly TT, Wilson DM, Buckingham BA
Exercise-associated hypoglycemia is a common adverse event in people with type 1 diabetes. Previous in silico testing by our group demonstrated superior exercise-associated hypoglycemia mitigation when a predictive low glucose suspend (PLGS) algorithm was augmented to incorporate activity data. The current study investigates the effectiveness of an accelerometer-augmented PLGS algorithm in an outpatient exercise protocol. Subjects with type 1 diabetes on insulin pump therapy participated in two structured soccer sessions, one utilizing the algorithm and the other using the subject's regular basal insulin rate. Each subject wore their own insulin pump and a Dexcom G4™ Platinum continuous glucose monitor (CGM); subjects on-algorithm also wore a Zephyr BioHarness™ 3 accelerometer. The algorithm utilized a Kalman filter with a 30-minute prediction horizon. Activity and CGM readings were manually entered into a spreadsheet and at five-minute intervals, the algorithm indicated whether the basal insulin infusion should be on or suspended; any changes were then implemented by study staff. The rate of hypoglycemia during and after exercise (until the following morning) was compared between groups. Eighteen subjects (mean age 13.4 ± 3.7 years) participated in two separate sessions 7-22 days apart. The difference in meter blood glucose levels between groups at each rest period did not achieve statistical significance at any time point. Hypoglycemia during the session was recorded in three on-algorithm subjects, compared to six off-algorithm subjects. In the postexercise monitoring period, hypoglycemia occurred in two subjects who were on-algorithm during the session and four subjects who were off-algorithm. The accelerometer-augmented algorithm failed to prevent exercise-associated hypoglycemia compared to subjects on their usual basal rates. A larger sample size may have achieved statistical significance. Further research involving an automated system, a larger sample size, and an algorithm design that favors longer periods of pump suspension is necessary.
PMID: 25231116 [PubMed - as supplied by publisher]
Clinical and immunologic predictors of death after an acute opportunistic infection: results from ACTG A5164.
HIV Clin Trials. 2014 Jul-Aug;15(4):133-9
Authors: Grant PM, Komarow L, Sanchez A, Sattler FR, Asmuth DM, Pollard RB, Zolopa AR
BACKGROUND: In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era.
OBJECTIVE: To determine clinical and immunological predictors of death after an OI.
METHODS: We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both.
RESULTS: The median CD4+ T-cell count in study participants at baseline was 29 cells/µL. Sixty-four percent of subjects had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death.
CONCLUSIONS: In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI.
PMID: 25143022 [PubMed - indexed for MEDLINE]
CT perfusion of the liver: principles and applications in oncology.
Radiology. 2014 Aug;272(2):322-44
Authors: Kim SH, Kamaya A, Willmann JK
With the introduction of molecularly targeted chemotherapeutics, there is an increasing need for defining new response criteria for therapeutic success because use of morphologic imaging alone may not fully assess tumor response. Computed tomographic (CT) perfusion imaging of the liver provides functional information about the microcirculation of normal parenchyma and focal liver lesions and is a promising technique for assessing the efficacy of various anticancer treatments. CT perfusion also shows promising results for diagnosing primary or metastatic tumors, for predicting early response to anticancer treatments, and for monitoring tumor recurrence after therapy. Many of the limitations of early CT perfusion studies performed in the liver, such as limited coverage, motion artifacts, and high radiation dose of CT, are being addressed by recent technical advances. These include a wide area detector with or without volumetric spiral or shuttle modes, motion correction algorithms, and new CT reconstruction technologies such as iterative algorithms. Although several issues related to perfusion imaging-such as paucity of large multicenter trials, limited accessibility of perfusion software, and lack of standardization in methods-remain unsolved, CT perfusion has now reached technical maturity, allowing for its use in assessing tumor vascularity in larger-scale prospective clinical trials. In this review, basic principles, current acquisition protocols, and pharmacokinetic models used for CT perfusion imaging of the liver are described. Various oncologic applications of CT perfusion of the liver are discussed and current challenges, as well as possible solutions, for CT perfusion are presented.
PMID: 25058132 [PubMed - indexed for MEDLINE]
Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors.
Cell. 2014 Jul 3;158(1):198-212
Authors: Rothwell PE, Fuccillo MV, Maxeiner S, Hayton SJ, Gokce O, Lim BK, Fowler SC, Malenka RC, Südhof TC
In humans, neuroligin-3 mutations are associated with autism, whereas in mice, the corresponding mutations produce robust synaptic and behavioral changes. However, different neuroligin-3 mutations cause largely distinct phenotypes in mice, and no causal relationship links a specific synaptic dysfunction to a behavioral change. Using rotarod motor learning as a proxy for acquired repetitive behaviors in mice, we found that different neuroligin-3 mutations uniformly enhanced formation of repetitive motor routines. Surprisingly, neuroligin-3 mutations caused this phenotype not via changes in the cerebellum or dorsal striatum but via a selective synaptic impairment in the nucleus accumbens/ventral striatum. Here, neuroligin-3 mutations increased rotarod learning by specifically impeding synaptic inhibition onto D1-dopamine receptor-expressing but not D2-dopamine receptor-expressing medium spiny neurons. Our data thus suggest that different autism-associated neuroligin-3 mutations cause a common increase in acquired repetitive behaviors by impairing a specific striatal synapse and thereby provide a plausible circuit substrate for autism pathophysiology.
PMID: 24995986 [PubMed - indexed for MEDLINE]
Glucose regulates mitochondrial motility via Milton modification by O-GlcNAc transferase.
Cell. 2014 Jul 3;158(1):54-68
Authors: Pekkurnaz G, Trinidad JC, Wang X, Kong D, Schwarz TL
Cells allocate substantial resources toward monitoring levels of nutrients that can be used for ATP generation by mitochondria. Among the many specialized cell types, neurons are particularly dependent on mitochondria due to their complex morphology and regional energy needs. Here, we report a molecular mechanism by which nutrient availability in the form of extracellular glucose and the enzyme O-GlcNAc Transferase (OGT), whose activity depends on glucose availability, regulates mitochondrial motility in neurons. Activation of OGT diminishes mitochondrial motility. We establish the mitochondrial motor-adaptor protein Milton as a required substrate for OGT to arrest mitochondrial motility by mapping and mutating the key O-GlcNAcylated serine residues. We find that the GlcNAcylation state of Milton is altered by extracellular glucose and that OGT alters mitochondrial motility in vivo. Our findings suggest that, by dynamically regulating Milton GlcNAcylation, OGT tailors mitochondrial dynamics in neurons based on nutrient availability.
PMID: 24995978 [PubMed - indexed for MEDLINE]
Prognostic importance of volumetric measurements in stage I lung adenocarcinoma.
Radiology. 2014 Aug;272(2):557-67
Authors: Yanagawa M, Tanaka Y, Leung AN, Morii E, Kusumoto M, Watanabe S, Watanabe H, Inoue M, Okumura M, Gyobu T, Ueda K, Honda O, Sumikawa H, Johkoh T, Tomiyama N
PURPOSE: To perform volumetric analysis of stage I lung adenocarcinomas by using an automated computer program and to determine value of volumetric computed tomographic (CT) measurements associated with prognostic factors and outcome.
MATERIALS AND METHODS: Consecutive patients (n = 145) with stage I lung adenocarcinoma who underwent surgery after preoperative chest CT were enrolled. By using volumetric automated computer-assisted analytic program, nodules were classified into three subgroups: pure ground glass, part solid, or solid. Total tumor volume, solid tumor volume, and percentage of solid volume of each cancer were calculated after eliminating vessel components. One radiologist measured the longest diameter of the solid tumor component and of total tumor with their ratio, which was defined as solid proportion. The value of these quantitative data by examining associations with pathologic prognostic factors and outcome measures (disease-free survival and overall survival) were analyzed with logistic regression and Cox proportional hazards regression models, respectively. Significant parameters identified at univariate analysis were included in the multiple analyses.
RESULTS: All 22 recurrences occurred in patients with nodules classified as part solid or solid. Multiple logistic regression analysis revealed that percentage of solid volume of 63% or greater was an independent indicator associated with pleural invasion (P = .01). Multiple Cox proportional hazards regression analysis revealed that percentage of solid volume of 63% or greater was a significant indicator of lower disease-free survival (hazard ratio, 18.45 [95% confidence interval: 4.34, 78.49]; P < .001). Both solid tumor volume of 1.5 cm(3) or greater and percentage of solid volume of 63% or greater were significant indicators of decreased overall survival (hazard ratio, 5.92 and 9.60, respectively [95% confidence interval: 1.17, 30.33 and 1.17, 78.91, respectively]; P = .034 and .036, respectively).
CONCLUSION: Two volumetric measurements (solid volume, ≥1.5 cm(3); percentage of solid volume, ≥63%) were found to be independent indicators associated with increased likelihood of recurrence and/or death in patients with stage I adenocarcinoma.
PMID: 24708191 [PubMed - indexed for MEDLINE]
Beyond the proteome: Mass Spectrometry Special Interest Group (MS-SIG) at ISMB/ECCB 2013.
Bioinformatics. 2014 Jul 15;30(14):2089-90
Authors: MS-SIG 2013 Organizers, Ryu SY, Payne SH, Schaab C, Xiao W
PMID: 24590439 [PubMed - indexed for MEDLINE]
Methods Cell Biol. 2014;120:39-51
Authors: Portran D
The following protocol describes a method to control the orientation and polarity of polymerizing microtubules (MTs). Reconstitution of specific geometries of dynamic MT networks is achieved using a ultraviolet (UV) micropatterning technique in combination with stabilized MT microseeds. The process is described in three main parts. First, the surface is passivated to avoid the non-specific absorption of proteins, using different polyethylene glycol (PEG)-based surface treatment. Second, specific adhesive surfaces (the micropatterns) are imprinted through a photomask using deep UVs. Lastly, MT microseeds are adhered to the micropatterns followed by MT polymerization.
PMID: 24484656 [PubMed - indexed for MEDLINE]
Hormonal regulation of microRNA expression in steroid producing cells of the ovary, testis and adrenal gland.
PLoS One. 2013;8(10):e78040
Authors: Hu Z, Shen WJ, Cortez Y, Tang X, Liu LF, Kraemer FB, Azhar S
BACKGROUND: Given the emerging roles of miRNAs as potential posttranscriptional/posttranslational regulators of the steroidogenic process in adrenocortical and gonadal cells, we sought to determine miRNA profiles in rat adrenals from animals treated with vehicle, ACTH, 17α-E2 or dexamethasone. Key observations were also confirmed using hormone (Bt2cAMP)-treated mouse Leydig tumor cells, MLTC-1, and primary rat ovarian granulosa cells.
METHODOLOGY: RNA was extracted from rat adrenal glands and miRNA profiles were established using microarray and confirmed with qRT-PCR. The expression of some of the hormone-sensitive miRNAs was quantified in MLTC-1 and granulosa cells after stimulation with Bt2cAMP. Targets of hormonally altered miRNAs were explored by qRT-PCR and Western blotting in adrenals and granulosa cells.
RESULTS: Adrenals from ACTH, 17α-E2 and dexamethasone treated rats exhibited miRNA profiles distinct from control animals. ACTH up-regulated the expression of miRNA-212, miRNA-182, miRNA-183, miRNA-132, and miRNA-96 and down-regulated the levels of miRNA-466b, miRNA-214, miRNA-503, and miRNA-27a. The levels of miR-212, miRNA-183, miRNA-182, miRNA-132, miRNA-370, miRNA-377, and miRNA-96 were up-regulated, whereas miR-125b, miRNA-200b, miR-122, miRNA-466b, miR-138, miRNA-214, miRNA-503 and miRNA27a were down-regulated in response to 17α-E2 treatment. Dexamethasone treatment decreased miRNA-200b, miR-122, miR-19a, miRNA-466b and miRNA27a levels, but increased miRNA-183 levels. Several adrenal miRNAs are subject to regulation by more than one hormone. Significant cAMP-induced changes in certain miRNAs were also noted in MLTC-1 and granulosa cells. Some of the hormone-induced miRNAs in steroidogenic cells were predicted to target proteins involved in lipid metabolism/steroidogenesis. We also obtained evidence that miR-132 and miRNA-214 inhibit the expression of SREBP-1c and LDLR, respectively.
CONCLUSION: Our results demonstrate that expression of a number of miRNAs in steroidogenic cells of the testis, ovary and adrenal glands is subject to hormonal regulation and that miRNAs and their regulation by specific hormones are likely to play a key role in posttranscriptional/posttranslational regulation of steroidogenesis.
PMID: 24205079 [PubMed - indexed for MEDLINE]
Intraoperative hyperthermia during cesarean section: a pertinent lesson.
Int J Obstet Anesth. 2014 Feb;23(1):96-7
Authors: Firago V, Brock-Utne JG
PMID: 23954017 [PubMed - indexed for MEDLINE]
High rate of preterm birth in pregnancies complicated by rheumatoid arthritis.
Am J Perinatol. 2014 Jan;31(1):9-14
Authors: Langen ES, Chakravarty EF, Liaquat M, El-Sayed YY, Druzin ML
OBJECTIVE: To describe the outcomes of pregnancies complicated by rheumatoid arthritis (RA) and to estimate potential associations between disease characteristics and pregnancy outcomes.
STUDY DESIGN: We reviewed all pregnancies complicated by RA delivered at our institution from June 2001 through June 2009. Fisher exact tests were used to calculate odds ratios. Univariable regression was performed using STATA 10.1 (StataCorp, College Station, TX). A p value of ≤ 0.05 was considered statistically significant.
RESULTS: Forty-six pregnancies in 40 women were reviewed. Sixty percent of pregnancies had evidence of disease flare and 28% delivered prior to 37 weeks. We did not identify associations between preterm birth and active disease at conception or during pregnancy. In univariate analysis, discontinuation of medication because of pregnancy was associated with a significantly earlier gestational age at delivery (362/7 versus 383/7 weeks, p = 0.022).
CONCLUSION: Women with RA may be at higher risk for preterm delivery.
PMID: 23359233 [PubMed - indexed for MEDLINE]
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