Recent Stanford Publications in PubMed
- Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells.Hendel A, Bak RO, Clark JT, Kennedy AB, Ryan DE, Roy S, Steinfeld I, Lunstad BD, Kaiser RJ, Wilkens AB, Bacchetta R, Tsalenko A, Dellinger D, Bruhn L, Porteus MHNat Biotechnol
- Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-β signaling and astrocyte functions.Schachtrup C, Ryu JK, Mammadzada K, Khan AS, Carlton PM, Perez A, Christian F, Le Moan N, Vagena E, Baeza-Raja B, Rafalski V, Chan JP, Nitschke R, Houslay MD, Ellisman MH, Wyss-Coray T, Palop JJ, Akassoglou KNat Neurosci
- Transvenous Approach to Intracranial Arteriovenous Malformations: Challenging the Axioms of Arteriovenous Malformation Therapy?Choudhri O, Ivan M, Lawton MTNeurosurgery
- Tapping Underserved Students to Reshape the Biomedical Workforce.Winkleby MA, Ned J, Crump CJ Community Med Health Educ
- An expedient synthesis of maraviroc (UK-427,857) via C-H functionalization.Bedell TA, Hone GA, Bois JD, Sorensen EJTetrahedron Lett
- RNA Binding Protein Nanos2 Organizes Post-transcriptional Buffering System to Retain Primitive State of Mouse Spermatogonial Stem Cells.Zhou Z, Shirakawa T, Ohbo K, Sada A, Wu Q, Hasegawa K, Saba R, Saga YDev Cell
- Epidural spinal involvement of Erdheim-Chester disease causing myelopathy.Hwang BY, Liu A, Kern J, Goodwin CR, Wolinsky JP, Desai AJ Clin Neurosci
- The anatomical and functional specialization of the fusiform gyrus.Weiner KS, Zilles KNeuropsychologia
- SPD-2/CEP192 and CDK Are Limiting for Microtubule-Organizing Center Function at the Centrosome.Yang R, Feldman JLCurr Biol
- Suppression of PGC-1α Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma.LaGory EL, Wu C, Taniguchi CM, Ding CC, Chi JT, von Eyben R, Scott DA, Richardson AD, Giaccia AJCell Rep
- The Nuclear PolyA-Binding Protein Nab2p Is Essential for mRNA Production.Schmid M, Olszewski P, Pelechano V, Gupta I, Steinmetz LM, Jensen THCell Rep
- Many Private Mutations Originate From The First Few Divisions Of A Human Colorectal Adenoma.Kang H, Salomon MP, Sottoriva A, Zhao J, Toy M, Press MF, Curtis C, Marjoram P, Siegmund K, Shibata DJ Pathol
- Classification models for subthreshold generalized anxiety disorder in a college population: Implications for prevention.Kanuri N, Taylor CB, Cohen JM, Newman MGJ Anxiety Disord
- Improving thermal dose accuracy in magnetic resonance-guided focused ultrasound surgery: Long-term thermometry using a prior baseline as a reference.Bitton RR, Webb TD, Pauly KB, Ghanouni PJ Magn Reson Imaging
- Utilization and likelihood of radiologic diagnostic imaging in patients with implantable cardiac defibrillators.Nazarian S, Reynolds MR, Ryan MP, Wolff SD, Mollenkopf SA, Turakhia MPJ Magn Reson Imaging
- Metabolome progression during early gut microbial colonization of gnotobiotic mice.Marcobal A, Yusufaly T, Higginbottom S, Snyder M, Sonnenburg JL, Mias GISci Rep
- Transcriptome sequencing reveals both neutral and adaptive genome dynamics in a marine invader.Tepolt CK, Palumbi SRMol Ecol
- Body mass index changes in youth in the first year after type 1 diabetes diagnosis.Gregg B, Connor CG, Ruedy KJ, Beck RW, Kollman C, Schatz D, Cengiz E, Harris B, Tamborlane WV, Klingensmith GJ, Lee JM, Pediatric Diabetes ConsortiumJ Pediatr
- Single mammalian cells compensate for differences in cellular volume and DNA copy number through independent global transcriptional mechanisms.Padovan-Merhar O, Nair GP, Biaesch AG, Mayer A, Scarfone S, Foley SW, Wu AR, Churchman LS, Singh A, Raj AMol Cell
- Diverse coupling of neurons to populations in sensory cortex.Okun M, Steinmetz NA, Cossell L, Iacaruso MF, Ko H, Barthó P, Moore T, Hofer SB, Mrsic-Flogel TD, Carandini M, Harris KDNature
- Balance between cell-substrate adhesion and myosin contraction determines the frequency of motility initiation in fish keratocytes.Barnhart E, Lee KC, Allen GM, Theriot JA, Mogilner AProc Natl Acad Sci U S A
- Reperfusion of very low cerebral blood volume lesion predicts parenchymal hematoma after endovascular therapy.Mishra NK, Christensen S, Wouters A, Campbell BC, Straka M, Mlynash M, Kemp S, Cereda CW, Bammer R, Marks MP, Albers GW, Lansberg MG, DEFUSE 2 InvestigatorsStroke
- Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents.Kovackova S, Chang L, Bekerman E, Neveu G, Barouch-Bentov R, Chaikuad A, Heroven C, Šála M, De Jonghe S, Knapp S, Einav S, Herdewijn PJ Med Chem
- Hypoxic induction of AKAP12 variant 2 shifts PKA-mediated protein phosphorylation to enhance migration and metastasis of melanoma cells.Finger EC, Castellini L, Rankin EB, Vilalta M, Krieg AJ, Jiang D, Banh A, Zundel W, Powell MB, Giaccia AJProc Natl Acad Sci U S A
- Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).Washam JB, Stevens SR, Lokhnygina Y, Halperin JL, Breithardt G, Singer DE, Mahaffey KW, Hankey GJ, Berkowitz SD, Nessel CC, Fox KA, Califf RM, Piccini JP, Patel MR, ROCKET AF Steering Committee and InvestigatorsLancet
- The genetic and mechanistic basis for variation in gene regulation.Pai AA, Pritchard JK, Gilad YPLoS Genet
- The global regulatory architecture of transcription during the Caulobacter cell cycle.Zhou B, Schrader JM, Kalogeraki VS, Abeliuk E, Dinh CB, Pham JQ, Cui ZZ, Dill DL, McAdams HH, Shapiro LPLoS Genet
- Longitudinal assessment of neuroanatomical and cognitive differences in young children with type 1 diabetes: association with hyperglycemia.Mauras N, Mazaika P, Buckingham B, Weinzimer S, White NH, Tsalikian E, Hershey T, Cato A, Cheng P, Kollman C, Beck RW, Ruedy K, Aye T, Fox L, Arbelaez AM, Wilson D, Tansey M, Tamborlane W, Peng D, Marzelli M, Winer KK, Reiss AL, Diabetes Research in Children Network (DirecNet)Diabetes
- Increased risk of cancer in infertile men: analysis of U.S. claims data.Eisenberg ML, Li S, Brooks JD, Cullen MR, Baker LCJ Urol
- Genetic polymorphisms in ESR1 and ESR2 genes, and risk of hypospadias in a multiethnic study population.Choudhry S, Baskin LS, Lammer EJ, Witte JS, Dasgupta S, Ma C, Surampalli A, Shen J, Shaw GM, Carmichael SLJ Urol
- The IPD and IMGT/HLA database: allele variant databases.Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SGNucleic Acids Res
- HIV diversity and drug resistance from plasma and non-plasma analytes in a large treatment programme in western Kenya.Kantor R, DeLong A, Balamane M, Schreier L, Lloyd RM, Injera W, Kamle L, Mambo F, Muyonga S, Katzenstein D, Hogan J, Buziba N, Diero LJ Int AIDS Soc
- Measurement of mast cell surface molecules by high-throughput immunophenotyping using transcription (HIT).Haddon DJ, Jarrell JA, Hughes MR, Snyder K, McNagny KM, Kattah MG, Utz PJMethods Mol Biol
- FcεRI expression and dynamics on mast cells.Rios EJ, Kalesnikoff JMethods Mol Biol
- Substrate selection for fundamental studies of electrocatalysts and photoelectrodes: inert potential windows in acidic, neutral, and basic electrolyte.Benck JD, Pinaud BA, Gorlin Y, Jaramillo TFPLoS One
- Not as good as you think? Trait positive emotion is associated with increased self-reported empathy but decreased empathic performance.Devlin HC, Zaki J, Ong DC, Gruber JPLoS One
- Transcriptome-wide mapping of pseudouridines: pseudouridine synthases modify specific mRNAs in S. cerevisiae.Lovejoy AF, Riordan DP, Brown POPLoS One
- Cutaneous ulceration in dermatomyositis: association with anti-melanoma differentiation-associated gene 5 antibodies and interstitial lung disease.Narang NS, Casciola-Rosen L, Li S, Chung L, Fiorentino DFArthritis Care Res (Hoboken)
- The complex portal--an encyclopaedia of macromolecular complexes.Meldal BH, Forner-Martinez O, Costanzo MC, Dana J, Demeter J, Dumousseau M, Dwight SS, Gaulton A, Licata L, Melidoni AN, Ricard-Blum S, Roechert B, Skyzypek MS, Tiwari M, Velankar S, Wong ED, Hermjakob H, Orchard SNucleic Acids Res
- Relationship of clinical course of illness variables to medical comorbidities in 900 adult outpatients with bipolar disorder.Post RM, Altshuler L, Leverich GS, Frye MA, Suppes T, McElroy SL, Keck PE, Nolen WA, Kupka RW, Grunze H, Rowe MCompr Psychiatry
- Millisecond flashes of light phase delay the human circadian clock during sleep.Zeitzer JM, Fisicaro RA, Ruby NF, Heller HCJ Biol Rhythms
- Design, synthesis and pharmacological evaluation of 2-(thiazol-2-amino)-4-arylaminopyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors.Liu Z, Yue X, Song Z, Peng X, Guo J, Ji Y, Cheng Z, Ding J, Ai J, Geng M, Zhang AEur J Med Chem
- The teaching practices inventory: a new tool for characterizing college and university teaching in mathematics and science.Wieman C, Gilbert SCBE Life Sci Educ
- Using an unconventional perfusion pattern in ear replantation-arterialization of the venous system.Momeni A, Parrett BM, Kuri MMicrosurgery
- Early vein reconstruction and right-to-left dissection for left-sided pancreatic tumors with portal vein occlusion.Cloyd JM, Dua MM, Visser BCJ Gastrointest Surg
- Assessing the health of the U.S. west coast with a regional-scale application of the Ocean Health Index.Halpern BS, Longo C, Scarborough C, Hardy D, Best BD, Doney SC, Katona SK, McLeod KL, Rosenberg AA, Samhouri JFPLoS One
- Foldscope: origami-based paper microscope.Cybulski JS, Clements J, Prakash MPLoS One
- Reply: 99mTc-MAA-based dosimetry for liver cancer treated using 90Y-loaded microspheres: known proof of effectiveness.Lam MG, Sze DYJ Nucl Med
- Differences in neural circuitry guiding behavioral responses to polarized light presented to either the dorsal or ventral retina in Drosophila.Velez MM, Gohl D, Clandinin TR, Wernet MFJ Neurogenet
- Tuberculosis treatment discontinuation and symptom persistence: an observational study of Bihar, India's public care system covering >100,000,000 inhabitants.Babiarz KS, Suen SC, Goldhaber-Fiebert JDBMC Public Health
- Ontology for the asexual development and anatomy of the colonial chordate Botryllus schlosseri.Manni L, Gasparini F, Hotta K, Ishizuka KJ, Ricci L, Tiozzo S, Voskoboynik A, Dauga DPLoS One
- Sedative and analgesic use on night and day shifts in a pediatric cardiovascular intensive care unit.Staveski SL, Tesoro TM, Cisco MJ, Roth SJ, Shin AYAACN Adv Crit Care
- Calculation of rate spectra from noisy time series data.Voelz VA, Pande VSProteins
Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells.
Nat Biotechnol. 2015 Jun 29;
Authors: Hendel A, Bak RO, Clark JT, Kennedy AB, Ryan DE, Roy S, Steinfeld I, Lunstad BD, Kaiser RJ, Wilkens AB, Bacchetta R, Tsalenko A, Dellinger D, Bruhn L, Porteus MH
CRISPR-Cas-mediated genome editing relies on guide RNAs that direct site-specific DNA cleavage facilitated by the Cas endonuclease. Here we report that chemical alterations to synthesized single guide RNAs (sgRNAs) enhance genome editing efficiency in human primary T cells and CD34(+) hematopoietic stem and progenitor cells. Co-delivering chemically modified sgRNAs with Cas9 mRNA or protein is an efficient RNA- or ribonucleoprotein (RNP)-based delivery method for the CRISPR-Cas system, without the toxicity associated with DNA delivery. This approach is a simple and effective way to streamline the development of genome editing with the potential to accelerate a wide array of biotechnological and therapeutic applications of the CRISPR-Cas technology.
PMID: 26121415 [PubMed - as supplied by publisher]
Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-β signaling and astrocyte functions.
Nat Neurosci. 2015 Jun 29;
Authors: Schachtrup C, Ryu JK, Mammadzada K, Khan AS, Carlton PM, Perez A, Christian F, Le Moan N, Vagena E, Baeza-Raja B, Rafalski V, Chan JP, Nitschke R, Houslay MD, Ellisman MH, Wyss-Coray T, Palop JJ, Akassoglou K
Astrocytes modulate neuronal activity and inhibit regeneration. We show that cleaved p75 neurotrophin receptor (p75(NTR)) is a component of the nuclear pore complex (NPC) required for glial scar formation and reduced gamma oscillations in mice via regulation of transforming growth factor (TGF)-β signaling. Cleaved p75(NTR) interacts with nucleoporins to promote Smad2 nucleocytoplasmic shuttling. Thus, NPC remodeling by regulated intramembrane cleavage of p75(NTR) controls astrocyte-neuronal communication in response to profibrotic factors.
PMID: 26120963 [PubMed - as supplied by publisher]
Transvenous Approach to Intracranial Arteriovenous Malformations: Challenging the Axioms of Arteriovenous Malformation Therapy?
Neurosurgery. 2015 Jun 26;
Authors: Choudhri O, Ivan M, Lawton MT
: A compartmental conceptualization of intracranial arteriovenous malformations (AVMs) allows recognition of feeding arteries, an intervening plexiform nidus, and draining veins. AVM therapy involves eliminating the nidus, which is the source of hemorrhage, without compromising normal arterial and venous drainage of the brain. Traditional methods of AVM therapy through microsurgery and endovascular embolization involve arterial devascularization, with preservation of AVM venous drainage, until the nidus is excluded. The transvenous approach in treating vascular malformations was popularized by successful treatment models for dural arteriovenous fistulas. More recently, high-flow intracranial AVMs are being managed with transvenous endovascular approaches, although this novel technique has its challenges and perils. We review the current literature on transvenous AVM therapy and highlight its role for AVM therapy in the present day.
ABBREVIATIONS: AVM, arteriovenous malformationsDAVF, dural arteriovenous fistulaTRENSCH, transvenous retrograde nidus sclerotherapy under controlled hypotensionVOG, vein of Galen.
PMID: 26120797 [PubMed - as supplied by publisher]
Tapping Underserved Students to Reshape the Biomedical Workforce.
J Community Med Health Educ. 2015 Apr;5(2):340
Authors: Winkleby MA, Ned J, Crump C
Low-income and underrepresented minority students remain a largely untapped source of new professionals that are increasingly needed to diversify and strengthen the biomedical workforce. Precollege enrichment programs offer a promising strategy to stop the "leak" in the biomedical pipeline. However, in the era of highly competitive science education funding, there is a lack of consensus about the elements that predict the long-term viability of such programs. In this commentary, the authors review the critical elements that contribute to the long-term viability of university-based precollege biomedical pipeline programs. Successful programs are built on a foundation of responding to local community workforce needs, have access to local universities that provide an organizational home, and offer a direct pipeline to strong undergraduate science training and support for graduate or professional training. Such programs have shown that there are substantial pools of diverse students who can thrive academically when given enrichment opportunities. Replication of pipeline programs with long-term viability will be instrumental in reaching the large numbers of talented underserved students who are needed to diversify and strengthen the biomedical workforce over the coming decades.
PMID: 26120496 [PubMed - as supplied by publisher]
An expedient synthesis of maraviroc (UK-427,857) via C-H functionalization.
Tetrahedron Lett. 2015 Jun 3;56(23):3620-3623
Authors: Bedell TA, Hone GA, Bois JD, Sorensen EJ
A new, concise synthesis of the CCR-5 receptor antagonist maraviroc (UK-427,857) from 3-phenyl-1-propanol has been completed in four steps featuring a site-selective C-H functionalization.
PMID: 26120216 [PubMed - as supplied by publisher]
RNA Binding Protein Nanos2 Organizes Post-transcriptional Buffering System to Retain Primitive State of Mouse Spermatogonial Stem Cells.
Dev Cell. 2015 Jun 24;
Authors: Zhou Z, Shirakawa T, Ohbo K, Sada A, Wu Q, Hasegawa K, Saba R, Saga Y
In many adult tissues, homeostasis relies on self-renewing stem cells that are primed for differentiation. The reconciliation mechanisms of these characteristics remain a fundamental question in stem cell biology. We propose that regulation at the post-transcriptional level is essential for homeostasis in murine spermatogonial stem cells (SSCs). Here, we show that Nanos2, an evolutionarily conserved RNA-binding protein, works with other cellular messenger ribonucleoprotein (mRNP) components to ensure the primitive status of SSCs through a dual mechanism that involves (1) direct recruitment and translational repression of genes that promote spermatogonial differentiation and (2) repression of the target of rapamycin complex 1 (mTORC1), a well-known negative pathway for SSC self-renewal, by sequestration of the core factor mTOR in mRNPs. This mechanism links mRNA turnover to mTORC1 signaling through Nanos2-containing mRNPs and establishes a post-transcriptional buffering system to facilitate SSC homeostasis in the fluctuating environment within the seminiferous tubule.
PMID: 26120033 [PubMed - as supplied by publisher]
Epidural spinal involvement of Erdheim-Chester disease causing myelopathy.
J Clin Neurosci. 2015 Jun 25;
Authors: Hwang BY, Liu A, Kern J, Goodwin CR, Wolinsky JP, Desai A
We present a 25-year-old woman with Erdheim-Chester disease (ECD) presenting with progressive myelopathy from multiple compressive spinal epidural lesions who required cervicothoracic decompression and fusion, and summarize the literature on epidural spinal involvement of ECD. ECD is a rare non-Langerhans histiocytosis affecting multiple organ systems through infiltration and characteristically causing multifocal osteosclerosis. Central nervous system involvement, particularly of the spine, is rare.
PMID: 26119978 [PubMed - as supplied by publisher]
The anatomical and functional specialization of the fusiform gyrus.
Neuropsychologia. 2015 Jun 25;
Authors: Weiner KS, Zilles K
The fusiform gyrus (FG) is commonly included in anatomical atlases and is considered a key structure for functionally-specialized computations of high-level vision such as face perception, object recognition, and reading. However, it is not widely known that the FG has a contentious history. In this review, we first provide a historical analysis of the discovery of the FG and why certain features, such as the mid-fusiform sulcus, were discovered and then forgotten. We then discuss how observer-independent methods for identifying cytoarchitectonical boundaries of the cortex revolutionized our understanding of cytoarchitecture and the correspondence between those boundaries and cortical folding patterns of the FG. We further explain that the co-occurrence between cortical folding patterns and cytoarchitectonical boundaries are more common than classically thought and also, are functionally meaningful especially on the FG and probably in high-level visual cortex more generally. We conclude by proposing a series of alternatives for how the anatomical organization of the FG can accommodate seemingly different theoretical aspects of functional processing, such as domain specificity and perceptual expertise.
PMID: 26119921 [PubMed - as supplied by publisher]
SPD-2/CEP192 and CDK Are Limiting for Microtubule-Organizing Center Function at the Centrosome.
Curr Biol. 2015 Jun 24;
Authors: Yang R, Feldman JL
The centrosome acts as the microtubule-organizing center (MTOC) during mitosis in animal cells. Microtubules are nucleated and anchored by γ-tubulin ring complexes (γ-TuRCs) embedded within the centrosome's pericentriolar material (PCM). The PCM is required for the localization of γ-TuRCs, and both are steadily recruited to the centrosome, culminating in a peak in MTOC function in metaphase . In differentiated cells, the centrosome is often attenuated as an MTOC and MTOC function is reassigned to non-centrosomal sites such as the apical membrane in epithelial cells, the nuclear envelope in skeletal muscle, and down the lengths of axons and dendrites in neurons [2-6]. Hyperactive MTOC function at the centrosome is associated with epithelial cancers and with invasive behavior in tumor cells [7-11]. Little is known about the mechanisms that limit MTOC activation at the centrosome. Here, we find that MTOC function at the centrosome is completely inactivated during cell differentiation in C. elegans embryonic intestinal cells and MTOC function is reassigned to the apical membrane. In cells that divide after differentiation, the cellular MTOC state switches between the membrane and the centrosome. Using cell fusion experiments in live embryos, we find that the centrosome MTOC state is dominant and that the inactive MTOC state of the centrosome is malleable; fusion of a mitotic cell to a differentiated or interphase cell results in rapid reactivation of the centrosome MTOC. We show that conversion of MTOC state involves the conserved centrosome protein SPD-2/CEP192 and CDK activity from the mitotic cell.
PMID: 26119750 [PubMed - as supplied by publisher]
Suppression of PGC-1α Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma.
Cell Rep. 2015 Jun 24;
Authors: LaGory EL, Wu C, Taniguchi CM, Ding CC, Chi JT, von Eyben R, Scott DA, Richardson AD, Giaccia AJ
Long believed to be a byproduct of malignant transformation, reprogramming of cellular metabolism is now recognized as a driving force in tumorigenesis. In clear cell renal cell carcinoma (ccRCC), frequent activation of HIF signaling induces a metabolic switch that promotes tumorigenesis. Here, we demonstrate that PGC-1α, a central regulator of energy metabolism, is suppressed in VHL-deficient ccRCC by a HIF/Dec1-dependent mechanism. In VHL wild-type cells, PGC-1α suppression leads to decreased expression of the mitochondrial transcription factor Tfam and impaired mitochondrial respiration. Conversely, PGC-1α expression in VHL-deficient cells restores mitochondrial function and induces oxidative stress. ccRCC cells expressing PGC-1α exhibit impaired tumor growth and enhanced sensitivity to cytotoxic therapies. In patients, low levels of PGC-1α expression are associated with poor outcome. These studies demonstrate that suppression of PGC-1α recapitulates key metabolic phenotypes of ccRCC and highlight the potential of targeting PGC-1α expression as a therapeutic modality for the treatment of ccRCC.
PMID: 26119730 [PubMed - as supplied by publisher]
The Nuclear PolyA-Binding Protein Nab2p Is Essential for mRNA Production.
Cell Rep. 2015 Jun 24;
Authors: Schmid M, Olszewski P, Pelechano V, Gupta I, Steinmetz LM, Jensen TH
Polyadenylation of mRNA is a key step in eukaryotic gene expression. However, despite the major impact of poly(A) tails on mRNA metabolism, the precise roles of poly(A)-binding proteins (PABPs) in nuclear mRNA biogenesis remain elusive. Here, we demonstrate that rapid nuclear depletion of the S. cerevisiae PABP Nab2p leads to a global loss of cellular mRNA, but not of RNA lacking poly(A) tails. Disappearance of mRNA is a nuclear event, but not due to decreased transcription. Instead, the absence of Nab2p results in robust nuclear mRNA decay by the ribonucleolytic RNA exosome in a polyadenylation-dependent process. We conclude that Nab2p is required to protect early mRNA and therefore constitutes a crucial nuclear mRNA biogenesis factor.
PMID: 26119729 [PubMed - as supplied by publisher]
Many Private Mutations Originate From The First Few Divisions Of A Human Colorectal Adenoma.
J Pathol. 2015 Jun 29;
Authors: Kang H, Salomon MP, Sottoriva A, Zhao J, Toy M, Press MF, Curtis C, Marjoram P, Siegmund K, Shibata D
Intratumoral mutational heterogeneity (ITH) or the presence of different private mutations in different parts of the same tumor is commonly observed in human tumors. The mechanisms generating such ITH are uncertain. Here we find ITH can be remarkably well-structured by measuring point mutations, chromosome copy numbers and DNA passenger methylation from opposite sides and individual glands of a 6 cm human colorectal adenoma. ITH was present between tumor sides and individual glands, but the private mutations were side specific and subdivided the adenoma into two major subclones. Furthermore, ITH disappeared within individual glands because the glands were clonal populations composed of cells with identical mutant genotypes. Despite mutation clonality, the glands were relatively old, diverse populations when their individual cells were compared for passenger methylation and by FISH. These observations can be organized into an expanding star-like ancestral tree with co-clonal expansion, where many private mutations and multiple related clones arise during the first few divisions. As a consequence, most detectable mutational ITH in the final tumor originates from the first few divisions. Much of the early history of a tumor, especially the first few divisions, may be embedded within the detectable ITH of tumor genomes.
PMID: 26119426 [PubMed - as supplied by publisher]
Classification models for subthreshold generalized anxiety disorder in a college population: Implications for prevention.
J Anxiety Disord. 2015 Jun 17;34:43-52
Authors: Kanuri N, Taylor CB, Cohen JM, Newman MG
Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders on college campuses and often goes unidentified and untreated. We propose a combined prevention and treatment model composed of evidence-based self-help (SH) and guided self-help (GSH) interventions to address this issue. To inform the development of this stepped-care model of intervention delivery, we evaluated results from a population-based anxiety screening of college students. A primary model was developed to illustrate how increasing levels of symptomatology could be linked to prevention/treatment interventions. We used screening data to propose four models of classification for populations at risk for GAD. We then explored the cost considerations of implementing this prevention/treatment stepped-care model. Among 2489 college students (mean age 19.1 years; 67% female), 8.0% (198/2489) met DSM-5 clinical criteria for GAD, in line with expected clinical rates for this population. At-risk Model 1 (subthreshold, but considerable symptoms of anxiety) identified 13.7% of students as potentially at risk for developing GAD. Model 2 (subthreshold, but high GAD symptom severity) identified 13.7%. Model 3 (subthreshold, but symptoms were distressing) identified 12.3%. Model 4 (subthreshold, but considerable worry) identified 17.4%. There was little overlap among these models, with a combined at-risk population of 39.4%. The efficiency of these models in identifying those truly at risk and the cost and efficacy of preventive interventions will determine if prevention is viable. Using Model 1 data and conservative cost estimates, we found that a preventive intervention effect size of even 0.2 could make a prevention/treatment model more cost-effective than existing models of "wait-and-treat."
PMID: 26119139 [PubMed - as supplied by publisher]
Improving thermal dose accuracy in magnetic resonance-guided focused ultrasound surgery: Long-term thermometry using a prior baseline as a reference.
J Magn Reson Imaging. 2015 Jun 26;
Authors: Bitton RR, Webb TD, Pauly KB, Ghanouni P
PURPOSE: To investigate thermal dose volume (TDV) and non-perfused volume (NPV) of magnetic resonance-guided focused ultrasound (MRgFUS) treatments in patients with soft tissue tumors, and describe a method for MR thermal dosimetry using a baseline reference.
MATERIALS AND METHODS: Agreement between TDV and immediate post treatment NPV was evaluated from MRgFUS treatments of five patients with biopsy-proven desmoid tumors. Thermometry data (gradient echo, 3T) were analyzed over the entire course of the treatments to discern temperature errors in the standard approach. The technique searches previously acquired baseline images for a match using 2D normalized cross-correlation and a weighted mean of phase difference images. Thermal dose maps and TDVs were recalculated using the matched baseline and compared to NPV.
RESULTS: TDV and NPV showed between 47%-91% disagreement, using the standard immediate baseline method for calculating TDV. Long-term thermometry showed a nonlinear local temperature accrual, where peak additional temperature varied between 4-13°C (mean = 7.8°C) across patients. The prior baseline method could be implemented by finding a previously acquired matching baseline 61% ± 8% (mean ± SD) of the time. We found 7%-42% of the disagreement between TDV and NPV was due to errors in thermometry caused by heat accrual. For all patients, the prior baseline method increased the estimated treatment volume and reduced the discrepancies between TDV and NPV (P = 0.023).
CONCLUSION: This study presents a mismatch between in-treatment and post treatment efficacy measures. The prior baseline approach accounts for local heating and improves the accuracy of thermal dose-predicted volume. J. Magn. Reson. Imaging 2015.
PMID: 26119129 [PubMed - as supplied by publisher]
Utilization and likelihood of radiologic diagnostic imaging in patients with implantable cardiac defibrillators.
J Magn Reson Imaging. 2015 Jun 27;
Authors: Nazarian S, Reynolds MR, Ryan MP, Wolff SD, Mollenkopf SA, Turakhia MP
PURPOSE: To examine imaging utilization in a matched cohort of patients with and without implantable cardioverter defibrillators (ICD) and to project magnetic resonance imaging (MRI) utilization over a 10-year period.
MATERIALS AND METHODS: The Truven Health MarketScan Commercial claims and Medicare Supplemental health insurance claims data were used to identify patients with continuous health plan enrollment in 2009-2012. Patients with ICDs were identified using ICD-9 and CPT codes, and matched to patients with the same demographic and comorbidity profile, but no record of device implantation. Diagnostic imaging utilization was compared across the matched cohorts, in total, by imaging categories, and in subpopulations of stroke, back pain, and joint pain. MRI use in the nonimplant group over the 4-year period was extrapolated out to 10 years for ICD-indicated patients.
RESULTS: A cohort of 18,770 matched patients were identified; average age 65.5 ± 13.38 and 21.9% female. ICD patients had significantly less MRI imaging (0.23 0.70 SD vs. 0.00 0.08 SD, P < 0.0001) than nonimplant patients. Among patients with records of stroke/transient ischemic attack (TIA) (ICD 5%, nonimplant 4%) and accompanying diagnostic imaging, 44% of nonimplant patients underwent MRI vs. 1% of ICD patients (P < 0.0001). Forecast models estimated that 53% to 64% of ICD-eligible patients may require an MRI within 10 years.
CONCLUSION: MRI utilization is lower in ICD patients compared to nonimplant patients, yet the burden of incident stroke/TIA, back, and joint pain suggests an unmet need for MR-conditional devices. J. Magn. Reson. Imaging 2015.
PMID: 26118943 [PubMed - as supplied by publisher]
Metabolome progression during early gut microbial colonization of gnotobiotic mice.
Sci Rep. 2015;5:11589
Authors: Marcobal A, Yusufaly T, Higginbottom S, Snyder M, Sonnenburg JL, Mias GI
The microbiome has been implicated directly in host health, especially host metabolic processes and development of immune responses. These are particularly important in infants where the gut first begins being colonized, and such processes may be modeled in mice. In this investigation we follow longitudinally the urine metabolome of ex-germ-free mice, which are colonized with two bacterial species, Bacteroides thetaiotaomicron and Bifidobacterium longum. High-throughput mass spectrometry profiling of urine samples revealed dynamic changes in the metabolome makeup, associated with the gut bacterial colonization, enabled by our adaptation of non-linear time-series analysis to urine metabolomics data. Results demonstrate both gradual and punctuated changes in metabolite production and that early colonization events profoundly impact the nature of small molecules circulating in the host. The identified small molecules are implicated in amino acid and carbohydrate metabolic processes, and offer insights into the dynamic changes occurring during the colonization process, using high-throughput longitudinal methodology.
PMID: 26118551 [PubMed - in process]
Transcriptome sequencing reveals both neutral and adaptive genome dynamics in a marine invader.
Mol Ecol. 2015 Jun 28;
Authors: Tepolt CK, Palumbi SR
Species invasions cause significant ecological and economic damage, and genetic information is important to understanding and managing invasive species. In the ocean, many invasive species have high dispersal and gene flow, lowering the discriminatory power of traditional genetic approaches. High-throughput sequencing holds tremendous promise for increasing resolution and illuminating the relative contributions of selection and drift in marine invasion, but has not yet been used to compare the diversity and dynamics of a high-dispersal invader in its native and invaded ranges. We test a transcriptome-based approach in the European green crab (Carcinus maenas), a widespread invasive species with high gene flow and a well-known invasion history, in two native and five invasive populations. A panel of 10,809 transcriptome-derived nuclear SNPs identified significant population structure among highly bottlenecked invasive populations that were previously undifferentiated with traditional markers. Comparing the full data set and a subset of 9,246 putatively neutral SNPs strongly suggested that non-neutral processes are the primary driver of population structure within the species' native range, while neutral processes appear to dominate in the invaded range. Non-neutral native range structure coincides with significant differences in intraspecific thermal tolerance, suggesting temperature as a potential selective agent. These results underline the importance of adaptation in shaping intraspecific differences even in high-gene flow marine invasive species. They also demonstrate that high-throughput approaches have broad utility in determining neutral structure in recent invasions of such species. Together, neutral and non-neutral data derived from high-throughput approaches may increase understanding of invasion dynamics in high-dispersal species. This article is protected by copyright. All rights reserved.
PMID: 26118396 [PubMed - as supplied by publisher]
Body mass index changes in youth in the first year after type 1 diabetes diagnosis.
J Pediatr. 2015 May;166(5):1265-1269.e1
Authors: Gregg B, Connor CG, Ruedy KJ, Beck RW, Kollman C, Schatz D, Cengiz E, Harris B, Tamborlane WV, Klingensmith GJ, Lee JM, Pediatric Diabetes Consortium
OBJECTIVES: To describe changes in weight and body mass index (BMI) during the first year following diagnosis of type 1 diabetes (T1D) and associations with demographic and clinical characteristics.
STUDY DESIGN: The Pediatric Diabetes Consortium includes 7 US centers with prospective longitudinal data from initial T1D diagnosis. This analysis includes 530 youth with diabetes duration of ≥1 year and measures of BMI at 3 and 12 months after diagnosis. BMI trajectory of participants and relationships between the change in BMI z-score from baseline (3 months) to 12 months with demographic characteristics, hemoglobin A1c at baseline, and insulin delivery mode at baseline were evaluated.
RESULTS: As a group, BMI z-scores increased sharply from diagnosis for 1-3 months but remained relatively stable from +0.51 at 3 months to +0.48 at 12 months. Children aged 2-<5 years experienced a significant positive change in BMI z-score between 3 and 12 months, and there was a similar trend among girls that did not reach statistical significance. No significant differences were found for race, socioeconomic status, or insulin delivery mode.
CONCLUSIONS: These data suggest that increased BMI during the first year of treatment of most youth with T1D reflects regain of weight lost before diagnosis. There is, however, a propensity toward additional weight gain in younger children and girls.
PMID: 25919735 [PubMed - indexed for MEDLINE]
Single mammalian cells compensate for differences in cellular volume and DNA copy number through independent global transcriptional mechanisms.
Mol Cell. 2015 Apr 16;58(2):339-52
Authors: Padovan-Merhar O, Nair GP, Biaesch AG, Mayer A, Scarfone S, Foley SW, Wu AR, Churchman LS, Singh A, Raj A
Individual mammalian cells exhibit large variability in cellular volume, even with the same absolute DNA content, and so must compensate for differences in DNA concentration in order to maintain constant concentration of gene expression products. Using single-molecule counting and computational image analysis, we show that transcript abundance correlates with cellular volume at the single-cell level due to increased global transcription in larger cells. Cell fusion experiments establish that increased cellular content itself can directly increase transcription. Quantitative analysis shows that this mechanism measures the ratio of cellular volume to DNA content, most likely through sequestration of a transcriptional factor to DNA. Analysis of transcriptional bursts reveals a separate mechanism for gene dosage compensation after DNA replication that enables proper transcriptional output during early and late S phase. Our results provide a framework for quantitatively understanding the relationships among DNA content, cell size, and gene expression variability in single cells.
PMID: 25866248 [PubMed - indexed for MEDLINE]
Diverse coupling of neurons to populations in sensory cortex.
Nature. 2015 May 28;521(7553):511-5
Authors: Okun M, Steinmetz NA, Cossell L, Iacaruso MF, Ko H, Barthó P, Moore T, Hofer SB, Mrsic-Flogel TD, Carandini M, Harris KD
A large population of neurons can, in principle, produce an astronomical number of distinct firing patterns. In cortex, however, these patterns lie in a space of lower dimension, as if individual neurons were "obedient members of a huge orchestra". Here we use recordings from the visual cortex of mouse (Mus musculus) and monkey (Macaca mulatta) to investigate the relationship between individual neurons and the population, and to establish the underlying circuit mechanisms. We show that neighbouring neurons can differ in their coupling to the overall firing of the population, ranging from strongly coupled 'choristers' to weakly coupled 'soloists'. Population coupling is largely independent of sensory preferences, and it is a fixed cellular attribute, invariant to stimulus conditions. Neurons with high population coupling are more strongly affected by non-sensory behavioural variables such as motor intention. Population coupling reflects a causal relationship, predicting the response of a neuron to optogenetically driven increases in local activity. Moreover, population coupling indicates synaptic connectivity; the population coupling of a neuron, measured in vivo, predicted subsequent in vitro estimates of the number of synapses received from its neighbours. Finally, population coupling provides a compact summary of population activity; knowledge of the population couplings of n neurons predicts a substantial portion of their n(2) pairwise correlations. Population coupling therefore represents a novel, simple measure that characterizes the relationship of each neuron to a larger population, explaining seemingly complex network firing patterns in terms of basic circuit variables.
PMID: 25849776 [PubMed - indexed for MEDLINE]
Balance between cell-substrate adhesion and myosin contraction determines the frequency of motility initiation in fish keratocytes.
Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5045-50
Authors: Barnhart E, Lee KC, Allen GM, Theriot JA, Mogilner A
Cells are dynamic systems capable of spontaneously switching among stable states. One striking example of this is spontaneous symmetry breaking and motility initiation in fish epithelial keratocytes. Although the biochemical and mechanical mechanisms that control steady-state migration in these cells have been well characterized, the mechanisms underlying symmetry breaking are less well understood. In this work, we have combined experimental manipulations of cell-substrate adhesion strength and myosin activity, traction force measurements, and mathematical modeling to develop a comprehensive mechanical model for symmetry breaking and motility initiation in fish epithelial keratocytes. Our results suggest that stochastic fluctuations in adhesion strength and myosin localization drive actin network flow rates in the prospective cell rear above a critical threshold. Above this threshold, high actin flow rates induce a nonlinear switch in adhesion strength, locally switching adhesions from gripping to slipping and further accelerating actin flow in the prospective cell rear, resulting in rear retraction and motility initiation. We further show, both experimentally and with model simulations, that the global levels of adhesion strength and myosin activity control the stability of the stationary state: The frequency of symmetry breaking decreases with increasing adhesion strength and increases with increasing myosin contraction. Thus, the relative strengths of two opposing mechanical forces--contractility and cell-substrate adhesion--determine the likelihood of spontaneous symmetry breaking and motility initiation.
PMID: 25848042 [PubMed - indexed for MEDLINE]
Reperfusion of very low cerebral blood volume lesion predicts parenchymal hematoma after endovascular therapy.
Stroke. 2015 May;46(5):1245-9
Authors: Mishra NK, Christensen S, Wouters A, Campbell BC, Straka M, Mlynash M, Kemp S, Cereda CW, Bammer R, Marks MP, Albers GW, Lansberg MG, DEFUSE 2 Investigators
BACKGROUND AND PURPOSE: Ischemic stroke patients with regional very low cerebral blood volume (VLCBV) on baseline imaging have increased risk of parenchymal hemorrhage (PH) after intravenous alteplase-induced reperfusion. We developed a method for automated detection of VLCBV and examined whether patients with reperfused-VLCBV are at increased risk of PH after endovascular reperfusion therapy.
METHODS: Receiver operating characteristic analysis was performed to optimize a relative CBV threshold associated with PH in patients from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2 (DEFUSE 2) study. Regional reperfused-VLCBV was defined as regions with low relative CBV on baseline imaging that demonstrated normal perfusion (Tmax <6 s) on coregistered early follow-up magnetic resonance imaging. The association between VLCBV, regional reperfused-VLCBV and PH was assessed in univariate and multivariate analyses.
RESULTS: In 91 patients, the greatest area under the curve for predicting PH occurred at an relative CBV threshold of <0.42 (area under the curve, 0.77). At this threshold, VLCBV lesion volume ≥3.55 mL optimally predicted PH with 94% sensitivity and 63% specificity. Reperfused-VLCBV lesion volume was more specific (0.74) and equally sensitive (0.94). In total, 18 patients developed PH, of whom 17 presented with VLCBV (39% versus 2%; P=0.001), all of them had regional reperfusion (47% versus 0%; P=0.01), and 71% received intravenous alteplase. VLCBV lesion (odds ratio, 33) and bridging with intravenous alteplase (odds ratio, 3.8) were independently associated with PH. In a separate model, reperfused-VLCBV remained the single independent predictor of PH (odds ratio, 53).
CONCLUSIONS: These results suggest that VLCBV can be used for risk stratification of patients scheduled to undergo endovascular therapy in trials and routine clinical practice.
PMID: 25828235 [PubMed - indexed for MEDLINE]
Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents.
J Med Chem. 2015 Apr 23;58(8):3393-410
Authors: Kovackova S, Chang L, Bekerman E, Neveu G, Barouch-Bentov R, Chaikuad A, Heroven C, Šála M, De Jonghe S, Knapp S, Einav S, Herdewijn P
Cyclin G associated kinase (GAK) emerged as a promising drug target for the treatment of viral infections. However, no potent and selective GAK inhibitors have been reported in the literature to date. This paper describes the discovery of isothiazolo[5,4-b]pyridines as selective GAK inhibitors, with the most potent congeners displaying low nanomolar binding affinity for GAK. Cocrystallization experiments revealed that these compounds behaved as classic type I ATP-competitive kinase inhibitors. In addition, we have demonstrated that these compounds exhibit a potent activity against hepatitis C virus (HCV) by inhibiting two temporally distinct steps in the HCV life cycle (i.e., viral entry and assembly). Hence, these GAK inhibitors represent chemical probes to study GAK function in different disease areas where GAK has been implicated (including viral infection, cancer, and Parkinson's disease).
PMID: 25822739 [PubMed - indexed for MEDLINE]
Hypoxic induction of AKAP12 variant 2 shifts PKA-mediated protein phosphorylation to enhance migration and metastasis of melanoma cells.
Proc Natl Acad Sci U S A. 2015 Apr 7;112(14):4441-6
Authors: Finger EC, Castellini L, Rankin EB, Vilalta M, Krieg AJ, Jiang D, Banh A, Zundel W, Powell MB, Giaccia AJ
Scaffold proteins are critical hubs within cells that have the ability to modulate upstream signaling molecules and their downstream effectors to fine-tune biological responses. Although they can serve as focal points for association of signaling molecules and downstream pathways that regulate tumorigenesis, little is known about how the tumor microenvironment affects the expression and activity of scaffold proteins. This study demonstrates that hypoxia, a common element of solid tumors harboring low oxygen levels, regulates expression of a specific variant of the scaffold protein AKAP12 (A-kinase anchor protein 12), AKAP12v2, in metastatic melanoma. In turn, through a kinome-wide phosphoproteomic and MS study, we demonstrate that this scaffolding protein regulates a shift in protein kinase A (PKA)-mediated phosphorylation events under hypoxia, causing alterations in tumor cell invasion and migration in vitro, as well as metastasis in an in vivo orthotopic model of melanoma. Mechanistically, the shift in AKAP12-dependent PKA-mediated phosphorylations under hypoxia is due to changes in AKAP12 localization vs. structural differences between its two variants. Importantly, our work defines a mechanism through which a scaffold protein can be regulated by the tumor microenvironment and further explains how a tumor cell can coordinate many critical signaling pathways that are essential for tumor growth through one individual scaffolding protein.
PMID: 25792458 [PubMed - indexed for MEDLINE]
Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).
Lancet. 2015 Jun 13;385(9985):2363-70
Authors: Washam JB, Stevens SR, Lokhnygina Y, Halperin JL, Breithardt G, Singer DE, Mahaffey KW, Hankey GJ, Berkowitz SD, Nessel CC, Fox KA, Califf RM, Piccini JP, Patel MR, ROCKET AF Steering Committee and Investigators
BACKGROUND: Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).
METHODS: For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study. Patients in ROCKET AF were recruited from 45 countries and had AF and risk factors putting them at moderate-to-high risk of stroke, with or without heart failure. We used Cox proportional hazards regression models adjusted for baseline characteristics and drugs to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death. ROCKET AF was registered with ClinicalTrials.gov, number NCT00403767.
FINDINGS: In 14,171 randomly assigned patients, digoxin was used at baseline in 5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p<0·0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5·41 vs 4·30 events per 100 patients-years; hazard ratio 1·17; 95% CI 1·04-1·32; p=0·0093), vascular death (3·55 vs 2·69 per 100 patient-years; 1·19; 1·03-1·39, p=0·0201), and sudden death (1·68 vs 1·12 events per 100 patient-years; 1·36; 1·08-1·70, p=0·0076).
INTERPRETATION: Digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. This association was independent of other measured prognostic factors, and although residual confounding could account for these results, these data show the possibility of digoxin having these effects. A randomised trial of digoxin in treatment of AF patients with and without heart failure is needed.
FUNDING: Janssen Research & Development and Bayer HealthCare AG.
PMID: 25749644 [PubMed - indexed for MEDLINE]
The genetic and mechanistic basis for variation in gene regulation.
PLoS Genet. 2015 Jan;11(1):e1004857
Authors: Pai AA, Pritchard JK, Gilad Y
It is now well established that noncoding regulatory variants play a central role in the genetics of common diseases and in evolution. However, until recently, we have known little about the mechanisms by which most regulatory variants act. For instance, what types of functional elements in DNA, RNA, or proteins are most often affected by regulatory variants? Which stages of gene regulation are typically altered? How can we predict which variants are most likely to impact regulation in a given cell type? Recent studies, in many cases using quantitative trait loci (QTL)-mapping approaches in cell lines or tissue samples, have provided us with considerable insight into the properties of genetic loci that have regulatory roles. Such studies have uncovered novel biochemical regulatory interactions and led to the identification of previously unrecognized regulatory mechanisms. We have learned that genetic variation is often directly associated with variation in regulatory activities (namely, we can map regulatory QTLs, not just expression QTLs [eQTLs]), and we have taken the first steps towards understanding the causal order of regulatory events (for example, the role of pioneer transcription factors). Yet, in most cases, we still do not know how to interpret overlapping combinations of regulatory interactions, and we are still far from being able to predict how variation in regulatory mechanisms is propagated through a chain of interactions to eventually result in changes in gene expression profiles.
PMID: 25569255 [PubMed - indexed for MEDLINE]
The global regulatory architecture of transcription during the Caulobacter cell cycle.
PLoS Genet. 2015 Jan;11(1):e1004831
Authors: Zhou B, Schrader JM, Kalogeraki VS, Abeliuk E, Dinh CB, Pham JQ, Cui ZZ, Dill DL, McAdams HH, Shapiro L
Each Caulobacter cell cycle involves differentiation and an asymmetric cell division driven by a cyclical regulatory circuit comprised of four transcription factors (TFs) and a DNA methyltransferase. Using a modified global 5' RACE protocol, we globally mapped transcription start sites (TSSs) at base-pair resolution, measured their transcription levels at multiple times in the cell cycle, and identified their transcription factor binding sites. Out of 2726 TSSs, 586 were shown to be cell cycle-regulated and we identified 529 binding sites for the cell cycle master regulators. Twenty-three percent of the cell cycle-regulated promoters were found to be under the combinatorial control of two or more of the global regulators. Previously unknown features of the core cell cycle circuit were identified, including 107 antisense TSSs which exhibit cell cycle-control, and 241 genes with multiple TSSs whose transcription levels often exhibited different cell cycle timing. Cumulatively, this study uncovered novel new layers of transcriptional regulation mediating the bacterial cell cycle.
PMID: 25569173 [PubMed - indexed for MEDLINE]
Longitudinal assessment of neuroanatomical and cognitive differences in young children with type 1 diabetes: association with hyperglycemia.
Diabetes. 2015 May;64(5):1770-9
Authors: Mauras N, Mazaika P, Buckingham B, Weinzimer S, White NH, Tsalikian E, Hershey T, Cato A, Cheng P, Kollman C, Beck RW, Ruedy K, Aye T, Fox L, Arbelaez AM, Wilson D, Tansey M, Tamborlane W, Peng D, Marzelli M, Winer KK, Reiss AL, Diabetes Research in Children Network (DirecNet)
Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.
PMID: 25488901 [PubMed - indexed for MEDLINE]
Increased risk of cancer in infertile men: analysis of U.S. claims data.
J Urol. 2015 May;193(5):1596-601
Authors: Eisenberg ML, Li S, Brooks JD, Cullen MR, Baker LC
PURPOSE: Aberrations in reproductive fitness may be a harbinger of medical diseases in men. Data suggest a higher risk of testicular cancer in infertile men. However, the relationship between infertility and other cancers remains uncertain.
MATERIALS AND METHODS: We analyzed subjects from the Truven Health MarketScan® claims database from 2001 to 2009. Infertile men were identified through diagnosis and treatment codes. Comparison groups were created of men who underwent vasectomy and a control cohort of men who were not infertile and had not undergone vasectomy. The incidence of cancer was compared to national U.S. estimates. Infertile men were also compared to men who underwent vasectomy and the control cohort using a Cox regression model.
RESULTS: A total of 76,083 infertile men were identified with an average age of 35.1 years. Overall 112,655 men who underwent vasectomy and 760,830 control men were assembled. Compared to age adjusted national averages, infertile, vasectomy and control subjects in the study cohorts had higher rates of all cancers and many individual cancers. In time to event analysis, infertile men had a higher risk of cancer than those who underwent vasectomy or controls. Infertile men had a higher risk of testis cancer, nonHodgkin lymphoma and all cancers than the vasectomy and control groups.
CONCLUSIONS: Consistent with prior reports, we identified an increased risk of testicular cancer in infertile men. The current data also suggest that infertile men are at an increased risk of all cancers in the years after infertility evaluation. Future research should focus on confirming these associations and elucidating pathways between infertility and cancer.
PMID: 25463997 [PubMed - indexed for MEDLINE]
Genetic polymorphisms in ESR1 and ESR2 genes, and risk of hypospadias in a multiethnic study population.
J Urol. 2015 May;193(5):1625-31
Authors: Choudhry S, Baskin LS, Lammer EJ, Witte JS, Dasgupta S, Ma C, Surampalli A, Shen J, Shaw GM, Carmichael SL
PURPOSE: Estrogenic endocrine disruptors acting via estrogen receptors α (ESR1) and β (ESR2) have been implicated in the etiology of hypospadias, a common congenital malformation of the male external genitalia. We determined the association of single nucleotide polymorphisms in ESR1 and ESR2 genes with hypospadias in a racially/ethnically diverse study population of California births.
MATERIALS AND METHODS: We investigated the relationship between hypospadias and 108 ESR1 and 36 ESR2 single nucleotide polymorphisms in 647 cases and 877 population based nonmalformed controls among infants born in selected California counties from 1990 to 2003. Subgroup analyses were performed by race/ethnicity (nonHispanic white and Hispanic subjects) and by hypospadias severity (mild to moderate and severe).
RESULTS: Odds ratios for 33 of the 108 ESR1 single nucleotide polymorphisms had p values less than 0.05 (p = 0.05 to 0.007) for risk of hypospadias. However, none of the 36 ESR2 single nucleotide polymorphisms was significantly associated. In stratified analyses the association results were consistent by disease severity but different sets of single nucleotide polymorphisms were significantly associated with hypospadias in nonHispanic white and Hispanic subjects. Due to high linkage disequilibrium across the single nucleotide polymorphisms, haplotype analyses were conducted and identified 6 haplotype blocks in ESR1 gene that had haplotypes significantly associated with an increased risk of hypospadias (OR 1.3 to 1.8, p = 0.04 to 0.00001). Similar to single nucleotide polymorphism analysis, different ESR1 haplotypes were associated with risk of hypospadias in nonHispanic white and Hispanic subjects. No significant haplotype association was observed for ESR2.
CONCLUSIONS: The data provide evidence that ESR1 single nucleotide polymorphisms and haplotypes influence the risk of hypospadias in white and Hispanic subjects, and warrant further examination in other study populations.
PMID: 25463985 [PubMed - indexed for MEDLINE]
The IPD and IMGT/HLA database: allele variant databases.
Nucleic Acids Res. 2015 Jan;43(Database issue):D423-31
Authors: Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SG
The Immuno Polymorphism Database (IPD) was developed to provide a centralized system for the study of polymorphism in genes of the immune system. Through the IPD project we have established a central platform for the curation and publication of locus-specific databases involved either directly or related to the function of the Major Histocompatibility Complex in a number of different species. We have collaborated with specialist groups or nomenclature committees that curate the individual sections before they are submitted to IPD for online publication. IPD consists of five core databases, with the IMGT/HLA Database as the primary database. Through the work of the various nomenclature committees, the HLA Informatics Group and in collaboration with the European Bioinformatics Institute we are able to provide public access to this data through the website http://www.ebi.ac.uk/ipd/. The IPD project continues to develop with new tools being added to address scientific developments, such as Next Generation Sequencing, and to address user feedback and requests. Regular updates to the website ensure that new and confirmatory sequences are dispersed to the immunogenetics community, and the wider research and clinical communities.
PMID: 25414341 [PubMed - indexed for MEDLINE]
HIV diversity and drug resistance from plasma and non-plasma analytes in a large treatment programme in western Kenya.
J Int AIDS Soc. 2014;17:19262
Authors: Kantor R, DeLong A, Balamane M, Schreier L, Lloyd RM, Injera W, Kamle L, Mambo F, Muyonga S, Katzenstein D, Hogan J, Buziba N, Diero L
INTRODUCTION: Antiretroviral resistance leads to treatment failure and resistance transmission. Resistance data in western Kenya are limited. Collection of non-plasma analytes may provide additional resistance information.
METHODS: We assessed HIV diversity using the REGA tool, transmitted resistance by the WHO mutation list and acquired resistance upon first-line failure by the IAS-USA mutation list, at the Academic Model Providing Access to Healthcare (AMPATH), a major treatment programme in western Kenya. Plasma and four non-plasma analytes, dried blood-spots (DBS), dried plasma-spots (DPS), ViveST(TM)-plasma (STP) and ViveST-blood (STB), were compared to identify diversity and evaluate sequence concordance.
RESULTS: Among 122 patients, 62 were treatment-naïve and 60 treatment-experienced; 61% were female, median age 35 years, median CD4 182 cells/µL, median viral-load 4.6 log10 copies/mL. One hundred and ninety-six sequences were available for 107/122 (88%) patients, 58/62 (94%) treatment-naïve and 49/60 (82%) treated; 100/122 (82%) plasma, 37/78 (47%) attempted DBS, 16/45 (36%) attempted DPS, 14/44 (32%) attempted STP from fresh plasma and 23/34 (68%) from frozen plasma, and 5/42 (12%) attempted STB. Plasma and DBS genotyping success increased at higher VL and shorter shipment-to-genotyping time. Main subtypes were A (62%), D (15%) and C (6%). Transmitted resistance was found in 1.8% of plasma sequences, and 7% combining analytes. Plasma resistance mutations were identified in 91% of treated patients, 76% NRTI, 91% NNRTI; 76% dual-class; 60% with intermediate-high predicted resistance to future treatment options; with novel mutation co-occurrence patterns. Nearly 88% of plasma mutations were identified in DBS, 89% in DPS and 94% in STP. Of 23 discordant mutations, 92% in plasma and 60% in non-plasma analytes were mixtures. Mean whole-sequence discordance from frozen plasma reference was 1.1% for plasma-DBS, 1.2% plasma-DPS, 2.0% plasma-STP and 2.3% plasma-STB. Of 23 plasma-STP discordances, one mutation was identified in plasma and 22 in STP (p<0.05). Discordance was inversely significantly related to VL for DBS.
CONCLUSIONS: In a large treatment programme in western Kenya, we report high HIV-1 subtype diversity; low plasma transmitted resistance, increasing when multiple analytes were combined; and high-acquired resistance with unique mutation patterns. Resistance surveillance may be augmented by using non-plasma analytes for lower-cost genotyping in resource-limited settings.
PMID: 25413893 [PubMed - indexed for MEDLINE]
Measurement of mast cell surface molecules by high-throughput immunophenotyping using transcription (HIT).
Methods Mol Biol. 2015;1220:381-400
Authors: Haddon DJ, Jarrell JA, Hughes MR, Snyder K, McNagny KM, Kattah MG, Utz PJ
Here we describe the application of a highly multiplexed proteomic assay, called HIT (high-throughput immunophenotyping using transcription), to analyze human mast cell surface antigens at rest and during stimulation. HIT allows analysis of up to 100 analytes, including surface antigens and intracellular phosphoproteins, transcription factors, and cytokines, in a single experiment. Briefly, anti-mouse monovalent Fab fragments are covalently conjugated with barcoded oligonucleotides to generate a panel of conjugates. The oligonucleotide-Fab fragment conjugates are bound to monoclonal primary antibodies, creating a cocktail of up to 48 unique barcoded primary antibodies. As few as 100,000 mast cells are stained with the cocktail and the barcodes of the bound primary antibodies are amplified by in vitro transcription with fluorescently labeled NTPs. The resulting barcoded transcripts are quantified using a microarray spotted with oligonucleotides that are complementary to the barcoded transcripts. Differences in levels of the barcoded transcripts correlate well with actual protein levels and are capable of detecting stimulation-dependent changes in protein levels. HIT is an invaluable, broad-spectrum approach for characterizing mast cell surface antigens, signaling molecules, transcription factors, and cytokines.
PMID: 25388264 [PubMed - indexed for MEDLINE]
FcεRI expression and dynamics on mast cells.
Methods Mol Biol. 2015;1220:239-55
Authors: Rios EJ, Kalesnikoff J
Mast cells are key effector and immunoregulatory cells in IgE-associated immune responses, including allergic disorders. IgE antibodies bind to the high-affinity IgE receptor, FcεRI, expressed on the surface of mast cells; antigen-induced cross-linking of FcεRI-bound IgE molecules activates the mast cell to release an array of proinflammatory and immunomodulatory mediators. Because mast cells often respond to very low levels of antigen in vivo, the level of FcεRI expressed on the surface of these cells is an important factor in determining the responsiveness of these cells to antigen. FcεRI surface expression is regulated by a number of processes, including FcεRI stabilization, FcεRI recycling, and antigen-induced internalization. Although members of the Rab family of small GTPases and the ubiquitin ligase, Cbl, have recently emerged as major regulators of many of the membrane trafficking events that govern FcεRI expression levels, the mechanisms and intracellular pathways that regulate FcεRI trafficking remain poorly defined. This chapter outlines a number of flow cytometry-based assays that can be used to investigate cell surface FcεRI expression and dynamics (stabilization, recycling, and internalization) on bone marrow-derived mast cells (BMCMCs), the most commonly used model system for studying mast cells in vitro. Given the importance of FcεRI levels to mast cell responsiveness and function, the characterization of FcεRI expression and dynamics on different mast cell populations is critical when trying to compare IgE-dependent processes between different mast cell populations.
PMID: 25388255 [PubMed - indexed for MEDLINE]
Substrate selection for fundamental studies of electrocatalysts and photoelectrodes: inert potential windows in acidic, neutral, and basic electrolyte.
PLoS One. 2014;9(10):e107942
Authors: Benck JD, Pinaud BA, Gorlin Y, Jaramillo TF
The selection of an appropriate substrate is an important initial step for many studies of electrochemically active materials. In order to help researchers with the substrate selection process, we employ a consistent experimental methodology to evaluate the electrochemical reactivity and stability of seven potential substrate materials for electrocatalyst and photoelectrode evaluation. Using cyclic voltammetry with a progressively increased scan range, we characterize three transparent conducting oxides (indium tin oxide, fluorine-doped tin oxide, and aluminum-doped zinc oxide) and four opaque conductors (gold, stainless steel 304, glassy carbon, and highly oriented pyrolytic graphite) in three different electrolytes (sulfuric acid, sodium acetate, and sodium hydroxide). We determine the inert potential window for each substrate/electrolyte combination and make recommendations about which materials may be most suitable for application under different experimental conditions. Furthermore, the testing methodology provides a framework for other researchers to evaluate and report the baseline activity of other substrates of interest to the broader community.
PMID: 25357131 [PubMed - indexed for MEDLINE]
Not as good as you think? Trait positive emotion is associated with increased self-reported empathy but decreased empathic performance.
PLoS One. 2014;9(10):e110470
Authors: Devlin HC, Zaki J, Ong DC, Gruber J
How is positive emotion associated with our ability to empathize with others? Extant research provides support for two competing predictions about this question. An empathy amplification hypothesis suggests positive emotion would be associated with greater empathy, as it often enhances other prosocial processes. A contrasting empathy attenuation hypothesis suggests positive emotion would be associated with lower empathy, because positive emotion promotes self-focused or antisocial behaviors. The present investigation tested these competing perspectives by examining associations between dispositional positive emotion and both subjective (i.e., self-report) and objective (i.e., task performance) measures of empathy. Findings revealed that although trait positive emotion was associated with increased subjective beliefs about empathic tendencies, it was associated with both increases and decreases in task-based empathic performance depending on the target's emotional state. More specifically, trait positive emotion was linked to lower overall empathic accuracy toward a high-intensity negative target, but also a higher sensitivity to emotion upshifts (i.e., shifts in emotion from negative to positive) toward positive targets. This suggests that trait positive affect may be associated with decreased objective empathy in the context of mood incongruent (i.e., negative) emotional stimuli, but may increase some aspects of empathic performance in the context of mood congruent (i.e., positive) stimuli. Taken together, these findings suggest that trait positive emotion engenders a compelling subjective-objective gap regarding its association with empathy, in being related to a heightened perception of empathic tendencies, despite being linked to mixed abilities in regards to empathic performance. (Word count: 242).
PMID: 25353635 [PubMed - indexed for MEDLINE]
Transcriptome-wide mapping of pseudouridines: pseudouridine synthases modify specific mRNAs in S. cerevisiae.
PLoS One. 2014;9(10):e110799
Authors: Lovejoy AF, Riordan DP, Brown PO
We developed a novel technique, called pseudouridine site identification sequencing (PSI-seq), for the transcriptome-wide mapping of pseudouridylation sites with single-base resolution from cellular RNAs based on the induced termination of reverse transcription specifically at pseudouridines following CMCT treatment. PSI-seq analysis of RNA samples from S. cerevisiae correctly detected all of the 43 known pseudouridines in yeast 18S and 25S ribosomal RNA with high specificity. Moreover, application of PSI-seq to the yeast transcriptome revealed the presence of site-specific pseudouridylation within dozens of mRNAs, including RPL11a, TEF1, and other genes implicated in translation. To identify the mechanisms responsible for mRNA pseudouridylation, we genetically deleted candidate pseudouridine synthase (Pus) enzymes and reconstituted their activities in vitro. These experiments demonstrated that the Pus1 enzyme was necessary and sufficient for pseudouridylation of RPL11a mRNA, whereas Pus4 modified TEF1 mRNA, and Pus6 pseudouridylated KAR2 mRNA. Finally, we determined that modification of RPL11a at Ψ -68 was observed in RNA from the related yeast S. mikitae, and Ψ -239 in TEF1 mRNA was maintained in S. mikitae as well as S. pombe, indicating that these pseudouridylations are ancient, evolutionarily conserved RNA modifications. This work establishes that site-specific pseudouridylation of eukaryotic mRNAs is a genetically programmed RNA modification that naturally occurs in multiple yeast transcripts via distinct mechanisms, suggesting that mRNA pseudouridylation may provide an important novel regulatory function. The approach and strategies that we report here should be generally applicable to the discovery of pseudouridylation, or other RNA modifications, in diverse biological contexts.
PMID: 25353621 [PubMed - indexed for MEDLINE]
Cutaneous ulceration in dermatomyositis: association with anti-melanoma differentiation-associated gene 5 antibodies and interstitial lung disease.
Arthritis Care Res (Hoboken). 2015 May;67(5):667-72
Authors: Narang NS, Casciola-Rosen L, Li S, Chung L, Fiorentino DF
OBJECTIVE: To identify clinical and serologic correlates of cutaneous ulcers in dermatomyositis (DM).
METHODS: We retrospectively examined a cohort of 152 DM patients. We compared the features of patients with ulcers to those without ulcers using chi-square or Fisher's exact tests and used univariate and multivariate logistic regression models to assess the association between ulcers and clinical features such as malignancy, interstitial lung disease (ILD), and amyopathic disease.
RESULTS: Forty-three patients (28%) had cutaneous ulcers. Nearly half the patients had ulcers present in more than 1 location: 24 (56%) had ulcers over the extensor surfaces of joints, 18 (42%) at the digital pulp or periungual areas, and 25 (58%) had ulcers located elsewhere. In univariate analysis ulcers were associated with Asian race, but not with other clinical and demographic features, including malignancy or ILD. In multivariate analysis ulcers were significantly associated with anti-melanoma differentiation gene 5 (anti-MDA5) antibodies (odds ratio 10.14, 95% confidence interval 1.95-52.78; P = 0.0059) and this was greatest for ulcers located at the digital pulp. In patients with cutaneous ulcers, ILD risk was specifically increased only in patients with anti-MDA5-positive antibodies.
CONCLUSION: We confirmed the strong association between anti-MDA5 antibodies and cutaneous ulcers, with the novel finding that the association of cutaneous ulcers with ILD depends upon the presence of anti-MDA5 antibodies. DM patients who display this cutaneous phenotype should undergo appropriate evaluation for ILD.
PMID: 25331610 [PubMed - indexed for MEDLINE]
The complex portal--an encyclopaedia of macromolecular complexes.
Nucleic Acids Res. 2015 Jan;43(Database issue):D479-84
Authors: Meldal BH, Forner-Martinez O, Costanzo MC, Dana J, Demeter J, Dumousseau M, Dwight SS, Gaulton A, Licata L, Melidoni AN, Ricard-Blum S, Roechert B, Skyzypek MS, Tiwari M, Velankar S, Wong ED, Hermjakob H, Orchard S
The IntAct molecular interaction database has created a new, free, open-source, manually curated resource, the Complex Portal (www.ebi.ac.uk/intact/complex), through which protein complexes from major model organisms are being collated and made available for search, viewing and download. It has been built in close collaboration with other bioinformatics services and populated with data from ChEMBL, MatrixDB, PDBe, Reactome and UniProtKB. Each entry contains information about the participating molecules (including small molecules and nucleic acids), their stoichiometry, topology and structural assembly. Complexes are annotated with details about their function, properties and complex-specific Gene Ontology (GO) terms. Consistent nomenclature is used throughout the resource with systematic names, recommended names and a list of synonyms all provided. The use of the Evidence Code Ontology allows us to indicate for which entries direct experimental evidence is available or if the complex has been inferred based on homology or orthology. The data are searchable using standard identifiers, such as UniProt, ChEBI and GO IDs, protein, gene and complex names or synonyms. This reference resource will be maintained and grow to encompass an increasing number of organisms. Input from groups and individuals with specific areas of expertise is welcome.
PMID: 25313161 [PubMed - indexed for MEDLINE]
Relationship of clinical course of illness variables to medical comorbidities in 900 adult outpatients with bipolar disorder.
Compr Psychiatry. 2015 Jan;56:21-8
Authors: Post RM, Altshuler L, Leverich GS, Frye MA, Suppes T, McElroy SL, Keck PE, Nolen WA, Kupka RW, Grunze H, Rowe M
BACKGROUND: Medical illnesses are highly comorbid with bipolar disorder, but their relationship to illness characteristics has not been previously delineated.
METHODS: The incidence of 34 medical conditions and 6 poor prognosis factors (PPFs) was derived from answers to a questionnaire in over 900 outpatients with bipolar disorder who gave informed consent. The relationship of PPFs to the number of medical comorbidities was examined by Mann-Whitney U, Pearson r, and logistic regression.
RESULTS: When examined individually, each of the 6 PPFs associated with an adverse course of bipolar disorder was significantly related to the number of medical comorbidities patients had. When age, gender, and independence of their relationships to each other were controlled for via regression, 3 of the PPFs remained significant (anxiety disorder, childhood abuse, and age of onset), and having 20 or more prior episodes was a strong trend. The number of PPFs was correlated with the number of comorbidities, although the above 3 PPFs show a similar magnitude of relationship.
CONCLUSION: A history of childhood adversity, early age of onset of bipolar disorder, and an anxiety comorbidity were independently related to the number of medical comorbidities that patients experienced as adults. While the nature and mechanisms of this linkage remain to be further explored, the findings indicate the need for greater attention to and treatment of these 3 PPFs in hopes of ameliorating both the adverse course of bipolar illness and the burden of medical comorbidities with which they are associated.
PMID: 25284280 [PubMed - indexed for MEDLINE]
Millisecond flashes of light phase delay the human circadian clock during sleep.
J Biol Rhythms. 2014 Oct;29(5):370-6
Authors: Zeitzer JM, Fisicaro RA, Ruby NF, Heller HC
The human circadian timing system is most sensitive to the phase-shifting effects of light during the biological nighttime, a time at which humans are most typically asleep. The overlap of sleep with peak sensitivity to the phase-shifting effects of light minimizes the effectiveness of using light as a countermeasure to circadian misalignment in humans. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. Using a 16-day, parallel group design, we examined whether a novel sequence of light flashes delivered during sleep could evoke phase changes in the circadian system without disrupting sleep. Healthy volunteers participated in a 2-week circadian stabilization protocol followed by a 2-night laboratory stay. During the laboratory session, they were exposed during sleep to either darkness (n = 7) or a sequence of 2-msec light flashes given every 30 sec (n = 6) from hours 2 to 3 after habitual bedtime. Changes in circadian timing (phase) and micro- and macroarchitecture of sleep were assessed. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm compared with the control dark condition (p < 0.05). Confirmation that the flashes penetrated the eyelids is presented by the occurrence of an evoked response in the EEG. Despite the robust effect on circadian timing, there were no large changes in either the amount or spectral content of sleep (p values > 0.30) during the flash stimulus. Exposing sleeping individuals to 0.24 sec of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. While a greater number of matched subjects and more research will be necessary to ascertain whether these light flashes affect sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans.
PMID: 25227334 [PubMed - indexed for MEDLINE]
Design, synthesis and pharmacological evaluation of 2-(thiazol-2-amino)-4-arylaminopyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors.
Eur J Med Chem. 2014 Oct 30;86:438-48
Authors: Liu Z, Yue X, Song Z, Peng X, Guo J, Ji Y, Cheng Z, Ding J, Ai J, Geng M, Zhang A
A series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) was developed by incorporation of a substituted 2-aminothiazole component as the C-2 substituent of the center pyrimidine core. Compound 5i showed highest potency of 12.4 nM against ALK and 24.1 nM against ALK gatekeeper mutation L1196M. Although only having moderate cellular potency in the SUP-M2 cells harboring NPM-ALK, compound 5i showed good kinase selectivity and dose-dependently inhibited phosphorylation of ALK and its down-stream signaling pathways.
PMID: 25200979 [PubMed - indexed for MEDLINE]
The teaching practices inventory: a new tool for characterizing college and university teaching in mathematics and science.
CBE Life Sci Educ. 2014;13(3):552-69
Authors: Wieman C, Gilbert S
We have created an inventory to characterize the teaching practices used in science and mathematics courses. This inventory can aid instructors and departments in reflecting on their teaching. It has been tested with several hundred university instructors and courses from mathematics and four science disciplines. Most instructors complete the inventory in 10 min or less, and the results allow meaningful comparisons of the teaching used for the different courses and instructors within a department and across different departments. We also show how the inventory results can be used to gauge the extent of use of research-based teaching practices, and we illustrate this with the inventory results for five departments. These results show the high degree of discrimination provided by the inventory, as well as its effectiveness in tracking the increase in the use of research-based teaching practices.
PMID: 25185237 [PubMed - indexed for MEDLINE]
Using an unconventional perfusion pattern in ear replantation-arterialization of the venous system.
Microsurgery. 2014 Nov;34(8):657-61
Authors: Momeni A, Parrett BM, Kuri M
Ear amputation is a devastating injury characterized by a conspicuous deformity that is not easily concealed and can result in tremendous psychological trauma in addition to the physical insult. While numerous different approaches have been proposed, microvascular replantation is widely considered to deliver the best esthetic outcome. In this article, the authors report a case in which an unconventional perfusion pattern (i.e., arterialization of the venous system) was chosen, as intraoperative anatomic conditions precluded conventional vascular reconstruction. A 25-year-old male patient sustained a human bite resulting in subtotal amputation of his left ear. In the setting of an adequate arterial donor vessel, that is, branch of the posterior auricular artery, and a single suitable recipient vein (0.4 mm), the decision was made to perform an end-to-end arterio-venous anastomosis without the use of vein grafts. Medicinal leeches were applied postoperatively to provide for venous drainage. The ear survived and the patient was discharged after 14 days. To the best of our knowledge, this is first case of a subtotal ear amputation that was successfully replanted by arterialization of the venous system without the use of vein grafts and with preservation of the superficial temporal vessels.
PMID: 25116223 [PubMed - indexed for MEDLINE]
Early vein reconstruction and right-to-left dissection for left-sided pancreatic tumors with portal vein occlusion.
J Gastrointest Surg. 2014 Nov;18(11):2034-7
Authors: Cloyd JM, Dua MM, Visser BC
Large left-sided pancreatic tumors are frequently associated with portal vein (PV) and/or superior mesenteric vein (SMV) occlusion. Traditionally, vein reconstruction is deferred until after removal of the tumor. However, division of venous collaterals, as is done in a typical left-to-right fashion, leads to progressive portal hypertension and increased risk of variceal hemorrhage during the dissection. Conversely, early PV/SMV resection and reconstruction restores mesenteric-portal flow and decompresses varices, thereby enabling a safer and easier right-to-left pancreatic resection. This "How I Do It" report describes the technique and advantages of a "reconstruction-first" approach for large left-sided pancreatic tumors with venous involvement and left-sided portal hypertension.
PMID: 25091848 [PubMed - indexed for MEDLINE]
Assessing the health of the U.S. west coast with a regional-scale application of the Ocean Health Index.
PLoS One. 2014;9(6):e98995
Authors: Halpern BS, Longo C, Scarborough C, Hardy D, Best BD, Doney SC, Katona SK, McLeod KL, Rosenberg AA, Samhouri JF
Management of marine ecosystems increasingly demands comprehensive and quantitative assessments of ocean health, but lacks a tool to do so. We applied the recently developed Ocean Health Index to assess ocean health in the relatively data-rich US west coast region. The overall region scored 71 out of 100, with sub-regions scoring from 65 (Washington) to 74 (Oregon). Highest scoring goals included tourism and recreation (99) and clean waters (87), while the lowest scoring goals were sense of place (48) and artisanal fishing opportunities (57). Surprisingly, even in this well-studied area data limitations precluded robust assessments of past trends in overall ocean health. Nonetheless, retrospective calculation of current status showed that many goals have declined, by up to 20%. In contrast, near-term future scores were on average 6% greater than current status across all goals and sub-regions. Application of hypothetical but realistic management scenarios illustrate how the Index can be used to predict and understand the tradeoffs among goals and consequences for overall ocean health. We illustrate and discuss how this index can be used to vet underlying assumptions and decisions with local stakeholders and decision-makers so that scores reflect regional knowledge, priorities and values. We also highlight the importance of ongoing and future monitoring that will provide robust data relevant to ocean health assessment.
PMID: 24941007 [PubMed - indexed for MEDLINE]
Foldscope: origami-based paper microscope.
PLoS One. 2014;9(6):e98781
Authors: Cybulski JS, Clements J, Prakash M
Here we describe an ultra-low-cost origami-based approach for large-scale manufacturing of microscopes, specifically demonstrating brightfield, darkfield, and fluorescence microscopes. Merging principles of optical design with origami enables high-volume fabrication of microscopes from 2D media. Flexure mechanisms created via folding enable a flat compact design. Structural loops in folded paper provide kinematic constraints as a means for passive self-alignment. This light, rugged instrument can survive harsh field conditions while providing a diversity of imaging capabilities, thus serving wide-ranging applications for cost-effective, portable microscopes in science and education.
PMID: 24940755 [PubMed - indexed for MEDLINE]
Reply: 99mTc-MAA-based dosimetry for liver cancer treated using 90Y-loaded microspheres: known proof of effectiveness.
J Nucl Med. 2014 Aug;55(8):1392-3
Authors: Lam MG, Sze DY
PMID: 24925882 [PubMed - indexed for MEDLINE]
Differences in neural circuitry guiding behavioral responses to polarized light presented to either the dorsal or ventral retina in Drosophila.
J Neurogenet. 2014 Sep-Dec;28(3-4):348-60
Authors: Velez MM, Gohl D, Clandinin TR, Wernet MF
Linearly polarized light (POL) serves as an important cue for many animals, providing navigational information, as well as directing them toward food sources and reproduction sites. Many insects detect the celestial polarization pattern, or the linearly polarized reflections off of surfaces, such as water. Much progress has been made toward characterizing both retinal detectors and downstream circuit elements responsible for celestial POL vision in different insect species, yet much less is known about the neural basis of how polarized reflections are detected. We previously established a novel, fully automated behavioral assay for studying the spontaneous orientation response of Drosophila melanogaster populations to POL stimuli presented to either the dorsal, or the ventral halves of the retina. We identified separate retinal detectors mediating these responses: the 'Dorsal Rim Area' (DRA), which had long been implicated in celestial POL vision, as well as a previously uncharacterized 'ventral polarization area' (VPA). In this study, we investigate whether DRA and VPA use the same or different downstream circuitry, for mediating spontaneous behavioral responses. We use homozygous mutants, or molecular genetic circuit-breaking tools (silencing, as well as rescue of synaptic activity), in combination with our behavioral paradigm. We show that responses to dorsal versus ventral stimulation involve previously characterized optic lobe neurons, like lamina monopolar cell L2 and medulla cell types Dm8/Tm5c. However, using different experimental conditions, we show that important differences exist between the requirement of these cell types downstream of DRA versus VPA. Therefore, while the neural circuits underlying behavioral responses to celestial and reflected POL cues share important building blocks, these elements play different functional roles within the network.
PMID: 24912584 [PubMed - indexed for MEDLINE]
Tuberculosis treatment discontinuation and symptom persistence: an observational study of Bihar, India's public care system covering >100,000,000 inhabitants.
BMC Public Health. 2014;14:418
Authors: Babiarz KS, Suen SC, Goldhaber-Fiebert JD
BACKGROUND: The effectiveness of India's TB control programs depend critically on patients completing appropriate treatment. Discontinuing treatment prior to completion can leave patients infectious and symptomatic. Developing strategies to reduce early discontinuation requires characterizing its patterns and their link to symptom persistence.
METHODS: The 2011 BEST-TB survey (360 clusters, 11 districts) sampled patients (n = 1007) from Bihar's public healthcare system who had initiated treatment >6 months prior to being interviewed, administering questionnaires to patients about TB treatment duration and symptoms, prior treatment, and sociodemographic characteristics. Multivariate logistic regression models estimated the risk of treatment discontinuation for these characteristics. Similar models estimated probabilities of symptom persistence to 25 weeks post-treatment initiation adjusting for the same predictors and treatment duration. All models included district fixed effects, robust standard errors, and adjustments for the survey sampling design. Treatment default timing and symptom persistence relied solely on self-report.
RESULTS: 24% of patients discontinued treatment prior to 25 weeks. Higher likelihood of discontinuation occurred in those who had failed to complete previous TB treatment episodes (aOR: 4.77 [95% CI: 1.98-11.53]) and those seeing multiple providers (3.67 per provider [1.94-6.95]). Symptoms persisted in 42% of patients discontinuing treatment within 5 weeks versus 28% for completing 25 weeks of treatment. Symptom persistence was more likely for those with prior TB treatment (aOR: 5.05 [1.90-13.38]); poorer patients (2.94 [1.51-5.72]); and women (1.79 [1.07-2.99]). Predictors for treatment discontinuation prior to 16 weeks were similar.
CONCLUSIONS: Premature TB treatment discontinuation and symptom persistence is particularly high among individuals who have failed to complete treatment for a prior episode. Strategies to identify and promote treatment completion in this group appear promising. Likewise, effective TB regimens of shortened duration currently in trials may eventually help to achieve higher treatment completion rates.
PMID: 24886314 [PubMed - indexed for MEDLINE]
Ontology for the asexual development and anatomy of the colonial chordate Botryllus schlosseri.
PLoS One. 2014;9(5):e96434
Authors: Manni L, Gasparini F, Hotta K, Ishizuka KJ, Ricci L, Tiozzo S, Voskoboynik A, Dauga D
Ontologies provide an important resource to integrate information. For developmental biology and comparative anatomy studies, ontologies of a species are used to formalize and annotate data that are related to anatomical structures, their lineage and timing of development. Here, we have constructed the first ontology for anatomy and asexual development (blastogenesis) of a bilaterian, the colonial tunicate Botryllus schlosseri. Tunicates, like Botryllus schlosseri, are non-vertebrates and the only chordate taxon species that reproduce both sexually and asexually. Their tadpole larval stage possesses structures characteristic of all chordates, i.e. a notochord, a dorsal neural tube, and gill slits. Larvae settle and metamorphose into individuals that are either solitary or colonial. The latter reproduce both sexually and asexually and these two reproductive modes lead to essentially the same adult body plan. The Botryllus schlosseri Ontology of Development and Anatomy (BODA) will facilitate the comparison between both types of development. BODA uses the rules defined by the Open Biomedical Ontologies Foundry. It is based on studies that investigate the anatomy, blastogenesis and regeneration of this organism. BODA features allow the users to easily search and identify anatomical structures in the colony, to define the developmental stage, and to follow the morphogenetic events of a tissue and/or organ of interest throughout asexual development. We invite the scientific community to use this resource as a reference for the anatomy and developmental ontology of B. schlosseri and encourage recommendations for updates and improvements.
PMID: 24789338 [PubMed - indexed for MEDLINE]
Sedative and analgesic use on night and day shifts in a pediatric cardiovascular intensive care unit.
AACN Adv Crit Care. 2014 Apr-Jun;25(2):114-8
Authors: Staveski SL, Tesoro TM, Cisco MJ, Roth SJ, Shin AY
INTRODUCTION: The use of sedative and analgesic medications is directly linked to patient outcomes. The practice of administering as-needed sedative or analgesic medications deserves further exploration. We hypothesized that important variations exist in the practice of administering as-needed medications in the intensive care unit (ICU). We aimed to determine the influence of time of day on the practice of administering as-needed sedative or analgesic medications to children in the ICU.
METHODS: Medication administration records of patients admitted to our pediatric cardiovascular ICU during a 4-month period were reviewed to determine the frequency and timing of as-needed medication usage by shift.
RESULTS: A total of 152 ICU admissions (1854 patient days) were reviewed. A significantly greater number of as-needed doses were administered during the night shift (fentanyl, P = .005; lorazepam, P = .03; midazolam, P = .0003; diphenhydramine, P = .0003; and chloral hydrate, P = .0006). These differences remained statistically significant after excluding doses given during the first 6 hours after cardiovascular surgery. Morphine administration was similar between shifts (P = .08).
CONCLUSIONS: We identified a pattern of increased administration of as-needed sedative or analgesic medications during nights. Further research is needed to identify the underlying causes of this practice variation.
PMID: 24752023 [PubMed - indexed for MEDLINE]
Calculation of rate spectra from noisy time series data.
Proteins. 2012 Feb;80(2):342-51
Authors: Voelz VA, Pande VS
As the resolution of experiments to measure folding kinetics continues to improve, it has become imperative to avoid bias that may come with fitting data to a predetermined mechanistic model. Toward this end, we present a rate spectrum approach to analyze timescales present in kinetic data. Computing rate spectra of noisy time series data via numerical discrete inverse Laplace transform is an ill-conditioned inverse problem, so a regularization procedure must be used to perform the calculation. Here, we show the results of different regularization procedures applied to noisy multiexponential and stretched exponential time series, as well as data from time-resolved folding kinetics experiments. In each case, the rate spectrum method recapitulates the relevant distribution of timescales present in the data, with different priors on the rate amplitudes naturally corresponding to common biases toward simple phenomenological models. These results suggest an attractive alternative to the "Occam's razor" philosophy of simply choosing models with the fewest number of relaxation rates.
PMID: 22095854 [PubMed - indexed for MEDLINE]
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