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- Impact of Adherence and Anthropometric Characteristics on Nevirapine Pharmacokinetics and Exposure among HIV-Infected Kenyan Children.Vreeman R, Nyandiko W, Liechty E, Busakhala N, Bartelink I, Savic R, Scanlon M, Ayaya S, Blaschke TJ Acquir Immune Defic Syndr
- Germ Cell Nuclear Factor Regulates Gametogenesis in Developing Gonads.Sabour D, Xu X, Chung AC, Le Menuet D, Ko K, Tapia N, Araúzo-Bravo MJ, Gentile L, Greber B, Hübner K, Sebastiano V, Wu G, Schöler HR, Cooney AJPLoS One
- Similar Prevalence of Low-Abundance Drug-Resistant Variants in Treatment-Naive Patients with Genotype 1a and 1b Hepatitis C Virus Infections as Determined by Ultradeep Pyrosequencing.Margeridon-Thermet S, Le Pogam S, Li L, Liu TF, Shulman N, Shafer RW, Najera IPLoS One
- Influence of interfacial rheology on drainage from curved surfaces.Bhamla MS, Giacomin CE, Balemans C, Fuller GGSoft Matter
- Detection of Osseous Metastasis by 18F-NaF/18F-FDG PET/CT Versus CT Alone.Sampath SC, Sampath SC, Mosci C, Lutz AM, Willmann JK, Mittra ES, Gambhir SS, Iagaru AClin Nucl Med
- Dynamical Phase Transitions Reveal Amyloid-like States on Protein Folding Landscapes.Weber JK, Jack RL, Schwantes CR, Pande VSBiophys J
- Complex Pathways in Folding of Protein G Explored by Simulation and Experiment.Lapidus LJ, Acharya S, Schwantes CR, Wu L, Shukla D, King M, DeCamp SJ, Pande VSBiophys J
- Retino-hypothalamic regulation of light-induced murine sleep.Muindi F, Zeitzer JM, Heller HCFront Syst Neurosci
- Changes in complex spike activity during classical conditioning.Rasmussen A, Jirenhed DA, Wetmore DZ, Hesslow GFront Neural Circuits
- Periostin is a novel therapeutic target that predicts and regulates glioma malignancy.Mikheev AM, Mikheeva SA, Trister AD, Tokita MJ, Emerson SN, Parada CA, Born DE, Carnemolla B, Frankel S, Kim DH, Oxford RG, Kosai Y, Tozer-Fink KR, Manning TC, Silber JR, Rostomily RCNeuro Oncol
- What can fruit flies teach us about karate?Yang HH, Clandinin TRElife
- Autism and attention-deficit/hyperactivity disorder among individuals with a family history of alcohol use disorders.Sundquist J, Sundquist K, Ji JElife
- A reflection of outcomes research and its impact on the practice of hand surgery.Curtin CM, Chung KCJ Hand Surg Eur Vol
- Haemophagocytic lymphohistiocytosis associated with coccidiomycosis.Ramsi M, Alvira C, Purohit P, Cornfield DBMJ Case Rep
- Integrative structure-function mapping of the nucleoporin Nup133 suggests a conserved mechanism for membrane anchoring of the nuclear pore complex.Kim SJ, Fernandez-Martinez J, Sampathkumar P, Martel A, Matsui T, Tsuruta H, Weiss T, Markina-Inarrairaegui A, Bonanno JB, Sauder JM, Burley SK, Almo SC, Rout M, Sali AMol Cell Proteomics
- Coordinating cell polarity: heading in the right direction?Axelrod JD, Bergmann DCDevelopment
- Leveraging Administrative Data for Program Evaluations: A Method for Linking Data Sets Without Unique Identifiers.Lorden AL, Radcliff TA, Jiang L, Horel SA, Smith ML, Lorig K, Howell BL, Whitelaw N, Ory MEval Health Prof
- The brassinosteroid signaling network-a paradigm of signal integration.Wang W, Bai MY, Wang ZYCurr Opin Plant Biol
- Authors' reply to de Vries.Lund M, Pasternak B, Wohlfahrt J, Melbye MBMJ
- Biomaterials for Craniofacial Bone Engineering.Tevlin R, McArdle A, Atashroo D, Walmsley GG, Senarath-Yapa K, Zielins ER, Paik KJ, Longaker MT, Wan DCJ Dent Res
- KIR diversity in Māori and Polynesians: populations in which HLA-B is not a significant KIR ligand.Nemat-Gorgani N, Edinur HA, Hollenbach JA, Traherne JA, Dunn PP, Chambers GK, Parham P, Norman PJImmunogenetics
- More with Less: Pancreas-Preserving Total Duodenectomy.Qadan M, Dua M, Worhunsky D, Triadafilopoulos G, Visser BDig Dis Sci
- Non-MalIg(G4)nant Biliary Obstruction: When the Pill Is Mightier than the Knife.Dua MM, Qadan M, Lutchman GA, Park WG, Triadafilopoulos G, Visser BCDig Dis Sci
- Relationship Among 25-Hydroxyvitamin D Concentrations, Insulin Action, and Cardiovascular Disease Risk in Patients With Essential Hypertension.Abbasi F, Feldman D, Caulfield MP, Hantash FM, Reaven GMAm J Hypertens
- RAPID EVOLUTION OF ADAPTIVE NICHE CONSTRUCTION IN EXPERIMENTAL MICROBIAL POPULATIONS.Callahan BJ, Fukami T, Fisher DSEvolution
- Solvent Effects on Polymer Sorting of Carbon Nanotubes with Applications in Printed Electronics.Wang H, Hsieh B, Jiménez-Osés G, Liu P, Tassone CJ, Diao Y, Lei T, Houk KN, Bao ZSmall
- Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States.Kwan A, Abraham RS, Currier R, Brower A, Andruszewski K, Abbott JK, Baker M, Ballow M, Bartoshesky LE, Bonilla FA, Brokopp C, Brooks E, Caggana M, Celestin J, Church JA, Comeau AM, Connelly JA, Cowan MJ, Cunningham-Rundles C, Dasu T, Dave N, De La Morena MT, Duffner U, Fong CT, Forbes L, Freedenberg D, Gelfand EW, Hale JE, Hanson IC, Hay BN, Hu D, Infante A, Johnson D, Kapoor N, Kay DM, Kohn DB, Lee R, Lehman H, Lin Z, Lorey F, Abdel-Mageed A, Manning A, McGhee S, Moore TB, Naides SJ, Notarangelo LD, Orange JS, Pai SY, Porteus M, Rodriguez R, Romberg N, Routes J, Ruehle M, Rubenstein A, Saavedra-Matiz CA, Scott G, Scott PM, Secord E, Seroogy C, Shearer WT, Siegel S, Silvers SK, Stiehm ER, Sugerman RW, Sullivan JL, Tanksley S, Tierce ML, Verbsky J, Vogel B, Walker R, Walkovich K, Walter JE, Wasserman RL, Watson MS, Weinberg GA, Weiner LB, Wood H, Yates AB, Puck JMJAMA
- Precise estimates of mutation rate and spectrum in yeast.Zhu YO, Siegal ML, Hall DW, Petrov DAProc Natl Acad Sci U S A
- Linkage disequilibrium and signatures of positive selection around LINE-1 retrotransposons in the human genome.Kuhn A, Ong YM, Cheng CY, Wong TY, Quake SR, Burkholder WFProc Natl Acad Sci U S A
- Wireless power transfer to deep-tissue microimplants.Ho JS, Yeh AJ, Neofytou E, Kim S, Tanabe Y, Patlolla B, Beygui RE, Poon ASProc Natl Acad Sci U S A
- Quenched disorder and vestigial nematicity in the pseudogap regime of the cuprates.Nie L, Tarjus G, Kivelson SAProc Natl Acad Sci U S A
- State medicaid coverage, ESRD incidence, and access to care.Kurella-Tamura M, Goldstein BA, Hall YN, Mitani AA, Winkelmayer WCJ Am Soc Nephrol
- Structure of the extended-spectrum class C β-lactamase ADC-1 from Acinetobacter baumannii.Bhattacharya M, Toth M, Antunes NT, Smith CA, Vakulenko SBActa Crystallogr D Biol Crystallogr
- Reconstructing Native American migrations from whole-genome and whole-exome data.Gravel S, Zakharia F, Moreno-Estrada A, Byrnes JK, Muzzio M, Rodriguez-Flores JL, Kenny EE, Gignoux CR, Maples BK, Guiblet W, Dutil J, Via M, Sandoval K, Bedoya G, 1000 Genomes Project, Oleksyk TK, Ruiz-Linares A, Burchard EG, Martinez-Cruzado JC, Bustamante CDPLoS Genet
- Genetic recombination is targeted towards gene promoter regions in dogs.Auton A, Rui Li Y, Kidd J, Oliveira K, Nadel J, Holloway JK, Hayward JJ, Cohen PE, Greally JM, Wang J, Bustamante CD, Boyko ARPLoS Genet
- Evidence that masking of synapsis imperfections counterbalances quality control to promote efficient meiosis.Mlynarczyk-Evans S, Roelens B, Villeneuve AMPLoS Genet
- Proteome-wide enrichment of proteins modified by lysine methylation.Carlson SM, Moore KE, Green EM, Martín GM, Gozani ONat Protoc
- Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy.McKay RR, Kroeger N, Xie W, Lee JL, Knox JJ, Bjarnason GA, MacKenzie MJ, Wood L, Srinivas S, Vaishampayan UN, Rha SY, Pal SK, Donskov F, Tantravahi SK, Rini BI, Heng DY, Choueiri TKEur Urol
- The effect of pedicle screw redirection after lateral wall breach--a biomechanical study using human lumbar vertebrae.Stauff MP, Freedman BA, Kim JH, Hamasaki T, Yoon ST, Hutton WCSpine J
- Detectable prostate-specific antigen Nadir during androgen-deprivation therapy predicts adverse prostate cancer-specific outcomes: results from the SEARCH database.Keto CJ, Aronson WJ, Terris MK, Presti JC, Kane CJ, Amling CL, Freedland SJEur Urol
- Impact of bone morphogenetic proteins on frequency of revision surgery, use of autograft bone, and total hospital charges in surgery for lumbar degenerative disease: review of the Nationwide Inpatient Sample from 2002 to 2008.Dagostino PR, Whitmore RG, Smith GA, Maltenfort MG, Ratliff JKSpine J
Impact of Adherence and Anthropometric Characteristics on Nevirapine Pharmacokinetics and Exposure among HIV-Infected Kenyan Children.
J Acquir Immune Defic Syndr. 2014 Aug 19;
Authors: Vreeman R, Nyandiko W, Liechty E, Busakhala N, Bartelink I, Savic R, Scanlon M, Ayaya S, Blaschke T
BACKGROUND: There are insufficient data on pediatric antiretroviral therapy (ART) pharmacokinetics (PK), particularly for children in low and middle-income countries.
METHODS: We conducted a prospective nevirapine (NVP) PK study among HIV-infected Kenyan children aged 3-13 years initiating an NVP-based ART regimen. NVP dose timing was measured through medication event monitors (MEMS®). Participants underwent 2 inpatient assessments; one at 4 to 8 weeks after ART initiation and one 3 to 4 months after ART initiation. Allometric scaling of oral clearance (CL)/bioavailability (F) and volume of distribution (Vd)/F values were computed. Nonlinear mixed effects modeling using the First Order Conditional Estimation with Interaction method was performed with covariates. The impact of adherence on time below minimum effective concentration (MEC) was assessed in the final PK model using MEMS® data and model-estimated individual parameters.
RESULTS: Among 21 children enrolled, mean age was 5.4 years and 57% were female. CL/F was 1.67 L/h and Vd/F was 3.8 L for a median child weighing 15 kg. Participants' age had a significant impact on CL/F (p <0.05), with an estimated decrease in CL of 6.2% for each one-year increase in age. Total body water percentage was significantly associated with Vd/F (p <0.001). No children had >10% of time below MEC when the PK model assumed perfect adherence compared to 10 children when adherence data were used.
CONCLUSIONS: Age and body composition were significantly associated with children's NVP PK parameters. ART adherence significantly impacted drug exposure over time, revealing sub-therapeutic windows that may lead to viral resistance.
PMID: 25140906 [PubMed - as supplied by publisher]
Germ Cell Nuclear Factor Regulates Gametogenesis in Developing Gonads.
PLoS One. 2014;9(8):e103985
Authors: Sabour D, Xu X, Chung AC, Le Menuet D, Ko K, Tapia N, Araúzo-Bravo MJ, Gentile L, Greber B, Hübner K, Sebastiano V, Wu G, Schöler HR, Cooney AJ
Expression of germ cell nuclear factor (GCNF; Nr6a1), an orphan member of the nuclear receptor gene family of transcription factors, during gastrulation and neurulation is critical for normal embryogenesis in mice. Gcnf represses the expression of the POU-domain transcription factor Oct4 (Pou5f1) during mouse post-implantation development. Although Gcnf expression is not critical for the embryonic segregation of the germ cell lineage, we found that sexually dimorphic expression of Gcnf in germ cells correlates with the expression of pluripotency-associated genes, such as Oct4, Sox2, and Nanog, as well as the early meiotic marker gene Stra8. To elucidate the role of Gcnf during mouse germ cell differentiation, we generated an ex vivo Gcnf-knockdown model in combination with a regulated CreLox mutation of Gcnf. Lack of Gcnf impairs normal spermatogenesis and oogenesis in vivo, as well as the derivation of germ cells from embryonic stem cells (ESCs) in vitro. Inactivation of the Gcnf gene in vivo leads to loss of repression of Oct4 expression in both male and female gonads.
PMID: 25140725 [PubMed - as supplied by publisher]
Similar Prevalence of Low-Abundance Drug-Resistant Variants in Treatment-Naive Patients with Genotype 1a and 1b Hepatitis C Virus Infections as Determined by Ultradeep Pyrosequencing.
PLoS One. 2014;9(8):e105569
Authors: Margeridon-Thermet S, Le Pogam S, Li L, Liu TF, Shulman N, Shafer RW, Najera I
BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) variants that confer resistance to direct-acting-antiviral agents (DAA) have been detected by standard sequencing technology in genotype (G) 1 viruses from DAA-naive patients. It has recently been shown that virological response rates are higher and breakthrough rates are lower in G1b infected patients than in G1a infected patients treated with certain classes of HCV DAAs. It is not known whether this corresponds to a difference in the composition of G1a and G1b HCV quasispecies in regards to the proportion of naturally occurring DAA-resistant variants before treatment.
METHODS: We used ultradeep pyrosequencing to determine the prevalence of low-abundance (<25% of the sequence reads) DAA-resistant variants in 191 NS3 and 116 NS5B isolates from 208 DAA-naive G1-infected patients.
RESULTS: A total of 3.5 million high-quality reads of ≥200 nucleotides were generated. The median coverage depth was 4150x and 4470x per NS3 and NS5B amplicon, respectively. Both G1a and G1b populations showed Shannon entropy distributions, with no difference between G1a and G1b in NS3 or NS5B region at the nucleotide level. A higher number of substitutions that confer resistance to protease inhibitors were observed in G1a isolates (mainly at amino acid 80 of the NS3 region). The prevalence of amino acid substitutions that confer resistance to NS5B non-nucleoside inhibitors was similar in G1a and G1b isolates. The NS5B S282T variant, which confers resistance to the polymerase inhibitors mericitabine and sofosbuvir, was not detected in any sample.
CONCLUSION: The quasispecies genetic diversity and prevalence of DAA-resistant variants was similar in G1a and G1b isolates and in both NS3 and NS5B regions, suggesting that this is not a determinant for the higher level of DAA resistance observed across G1a HCV infected patients upon treatment.
PMID: 25140696 [PubMed - as supplied by publisher]
Influence of interfacial rheology on drainage from curved surfaces.
Soft Matter. 2014 Aug 20;10(36):6917-6925
Authors: Bhamla MS, Giacomin CE, Balemans C, Fuller GG
Thin lubrication flows accompanying drainage from curved surfaces surround us (e.g., the drainage of the tear film on our eyes). These draining aqueous layers are normally covered with surface-active molecules that render the free surface viscoelastic. The non-Newtonian character of these surfaces fundamentally alters the dynamics of drainage. We show that increased film stability during drainage can occur as a consequence of enhanced surface rheology. Increasing the surfactant layer viscosity decreases the rate of drainage; however, this retarding influence is most pronounced when the insoluble surfactant layer has significant elasticity. We also present a simple theoretical model that offers qualitative support to our experimental findings.
PMID: 25140576 [PubMed - as supplied by publisher]
Detection of Osseous Metastasis by 18F-NaF/18F-FDG PET/CT Versus CT Alone.
Clin Nucl Med. 2014 Aug 19;
Authors: Sampath SC, Sampath SC, Mosci C, Lutz AM, Willmann JK, Mittra ES, Gambhir SS, Iagaru A
PURPOSE: Sodium fluoride PET (F-NaF) has recently reemerged as a valuable method for detection of osseous metastasis, with recent work highlighting the potential of coadministered F-NaF and F-FDG PET/CT in a single combined imaging examination. We further examined the potential of such combined examinations by comparing dual tracer F-NaF/F-FDG PET/CT with CT alone for detection of osseous metastasis.
PATIENTS AND METHODS: Seventy-five participants with biopsy-proven malignancy were consecutively enrolled from a single center and underwent combined F-NaF/F-FDG PET/CT and diagnostic CT scans. PET/CT as well as CT only images were reviewed in blinded fashion and compared with the results of clinical, imaging, or histological follow-up as a truth standard.
RESULTS: Sensitivity of the combined F-NaF/F-FDG PET/CT was higher than that of CT alone (97.4% vs 66.7%). CT and F-NaF/F-FDG PET/CT were concordant in 73% of studies. Of 20 discordant cases, F-NaF/F-FDG PET/CT was correct in 19 (95%). Three cases were interpreted concordantly but incorrectly, and all 3 were false positives. A single case of osseous metastasis was detected by CT alone, but not by F-NaF/F-FDG PET/CT.
CONCLUSIONS: Combined F-NaF/F-FDG PET/CT outperforms CT alone and is highly sensitive and specific for detection of osseous metastases. The concordantly interpreted false-positive cases demonstrate the difficulty of distinguishing degenerative from malignant disease, whereas the single case of metastasis seen on CT but not PET highlights the need for careful review of CT images in multimodality studies.
PMID: 25140557 [PubMed - as supplied by publisher]
Dynamical Phase Transitions Reveal Amyloid-like States on Protein Folding Landscapes.
Biophys J. 2014 Aug 19;107(4):974-982
Authors: Weber JK, Jack RL, Schwantes CR, Pande VS
Developing an understanding of protein misfolding processes presents a crucial challenge for unlocking the mysteries of human disease. In this article, we present our observations of β-sheet-rich misfolded states on a number of protein dynamical landscapes investigated through molecular dynamics simulation and Markov state models. We employ a nonequilibrium statistical mechanical theory to identify the glassy states in a protein's dynamics, and we discuss the nonnative, β-sheet-rich states that play a distinct role in the slowest dynamics within seven protein folding systems. We highlight the fundamental similarity between these states and the amyloid structures responsible for many neurodegenerative diseases, and we discuss potential consequences for mechanisms of protein aggregation and intermolecular amyloid formation.
PMID: 25140433 [PubMed - as supplied by publisher]
Complex Pathways in Folding of Protein G Explored by Simulation and Experiment.
Biophys J. 2014 Aug 19;107(4):947-955
Authors: Lapidus LJ, Acharya S, Schwantes CR, Wu L, Shukla D, King M, DeCamp SJ, Pande VS
The B1 domain of protein G has been a classic model system of folding for decades, the subject of numerous experimental and computational studies. Most of the experimental work has focused on whether the protein folds via an intermediate, but the evidence is mostly limited to relatively slow kinetic observations with a few structural probes. In this work we observe folding on the submillisecond timescale with microfluidic mixers using a variety of probes including tryptophan fluorescence, circular dichroism, and photochemical oxidation. We find that each probe yields different kinetics and compare these observations with a Markov State Model constructed from large-scale molecular dynamics simulations and find a complex network of states that yield different kinetics for different observables. We conclude that there are many folding pathways before the final folding step and that these paths do not have large free energy barriers.
PMID: 25140430 [PubMed - as supplied by publisher]
Retino-hypothalamic regulation of light-induced murine sleep.
Front Syst Neurosci. 2014;8:135
Authors: Muindi F, Zeitzer JM, Heller HC
The temporal organization of sleep is regulated by an interaction between the circadian clock and homeostatic processes. Light indirectly modulates sleep through its ability to phase shift and entrain the circadian clock. Light can also exert a direct, circadian-independent effect on sleep. For example, acute exposure to light promotes sleep in nocturnal animals and wake in diurnal animals. The mechanisms whereby light directly influences sleep and arousal are not well understood. In this review, we discuss the direct effect of light on sleep at the level of the retina and hypothalamus in rodents. We review murine data from recent publications showing the roles of rod-, cone- and melanopsin-based photoreception on the initiation and maintenance of light-induced sleep. We also present hypotheses about hypothalamic mechanisms that have been advanced to explain the acute control of sleep by light. Specifically, we review recent studies assessing the roles of the ventrolateral preoptic area (VLPO) and the suprachiasmatic nucleus (SCN). We also discuss how light might differentially promote sleep and arousal in nocturnal and diurnal animals respectively. Lastly, we suggest new avenues for research on this topic which is still in its early stages.
PMID: 25140132 [PubMed]
Changes in complex spike activity during classical conditioning.
Front Neural Circuits. 2014;8:90
Authors: Rasmussen A, Jirenhed DA, Wetmore DZ, Hesslow G
The cerebellar cortex is necessary for adaptively timed conditioned responses (CRs) in eyeblink conditioning. During conditioning, Purkinje cells acquire pause responses or "Purkinje cell CRs" to the conditioned stimuli (CS), resulting in disinhibition of the cerebellar nuclei (CN), allowing them to activate motor nuclei that control eyeblinks. This disinhibition also causes inhibition of the inferior olive (IO), via the nucleo-olivary pathway (N-O). Activation of the IO, which relays the unconditional stimulus (US) to the cortex, elicits characteristic complex spikes in Purkinje cells. Although Purkinje cell activity, as well as stimulation of the CN, is known to influence IO activity, much remains to be learned about the way that learned changes in simple spike firing affects the IO. In the present study, we analyzed changes in simple and complex spike firing, in extracellular Purkinje cell records, from the C3 zone, in decerebrate ferrets undergoing training in a conditioning paradigm. In agreement with the N-O feedback hypothesis, acquisition resulted in a gradual decrease in complex spike activity during the conditioned stimulus, with a delay that is consistent with the long N-O latency. Also supporting the feedback hypothesis, training with a short interstimulus interval (ISI), which does not lead to acquisition of a Purkinje cell CR, did not cause a suppression of complex spike activity. In contrast, observations that extinction did not lead to a recovery in complex spike activity and the irregular patterns of simple and complex spike activity after the conditioned stimulus are less conclusive.
PMID: 25140129 [PubMed - in process]
Periostin is a novel therapeutic target that predicts and regulates glioma malignancy.
Neuro Oncol. 2014 Aug 19;
Authors: Mikheev AM, Mikheeva SA, Trister AD, Tokita MJ, Emerson SN, Parada CA, Born DE, Carnemolla B, Frankel S, Kim DH, Oxford RG, Kosai Y, Tozer-Fink KR, Manning TC, Silber JR, Rostomily RC
BACKGROUND: Periostin is a secreted matricellular protein critical for epithelial-mesenchymal transition and carcinoma metastasis. In glioblastoma, it is highly upregulated compared with normal brain, and existing reports indicate potential prognostic and functional importance in glioma. However, the clinical implications of periostin expression and function related to its therapeutic potential have not been fully explored.
METHODS: Periostin expression levels and patterns were examined in human glioma cells and tissues by quantitative real-time PCR and immunohistochemistry and correlated with glioma grade, type, recurrence, and survival. Functional assays determined the impact of altering periostin expression and function on cell invasion, migration, adhesion, and glioma stem cell activity and tumorigenicity. The prognostic and functional relevance of periostin and its associated genes were analyzed using the TCGA and REMBRANDT databases and paired recurrent glioma samples.
RESULTS: Periostin expression levels correlated directly with tumor grade and recurrence, and inversely with survival, in all grades of adult human glioma. Stromal deposition of periostin was detected only in grade IV gliomas. Secreted periostin promoted glioma cell invasion and adhesion, and periostin knockdown markedly impaired survival of xenografted glioma stem cells. Interactions with αvβ3 and αvβ5 integrins promoted adhesion and migration, and periostin abrogated cytotoxicity of the αvβ3/β5 specific inhibitor cilengitide. Periostin-associated gene signatures, predominated by matrix and secreted proteins, corresponded to patient prognosis and functional motifs related to increased malignancy.
CONCLUSION: Periostin is a robust marker of glioma malignancy and potential tumor recurrence. Abrogation of glioma stem cell tumorigenicity after periostin inhibition provides support for exploring the therapeutic impact of targeting periostin.
PMID: 25140038 [PubMed - as supplied by publisher]
What can fruit flies teach us about karate?
Authors: Yang HH, Clandinin TR
Understanding the logic behind how a fruit fly's brain tells it to groom its body parts in a stereotyped order might help us understand other behaviours that also involve a series of actions.
PMID: 25139958 [PubMed - in process]
Autism and attention-deficit/hyperactivity disorder among individuals with a family history of alcohol use disorders.
Authors: Sundquist J, Sundquist K, Ji J
Recent studies suggest de novo mutations may involve the pathogenesis of autism and attention-deficit/hyperactivity disorder (ADHD). Based on the evidence that excessive alcohol consumption may be associated with an increased rate of de novo mutations in germ cells (sperms or eggs), we examine here whether the risks of autism and ADHD are increased among individuals with a family history of alcohol use disorders (AUDs). The standardized incidence ratios (SIRs) of autism and ADHD among individuals with a biological parental history of AUDs were 1.39 (95% CI 1.34-1.44) and 2.19 (95% CI 2.15-2.23), respectively, compared to individuals without an affected parent. Among offspring whose parents were diagnosed with AUDs before their birth, the corresponding risks were 1.46 (95% CI 1.36-1.58) and 2.70 (95% CI 2.59-2.81), respectively. Our study calls for extra surveillance for children with a family history of AUDs, and further studies examining the underlying mechanisms are needed.DOI: http://dx.doi.org/10.7554/eLife.02917.001.
PMID: 25139954 [PubMed - in process]
A reflection of outcomes research and its impact on the practice of hand surgery.
J Hand Surg Eur Vol. 2014 Sep;39(7):790-3
Authors: Curtin CM, Chung KC
PMID: 25139931 [PubMed - in process]
Haemophagocytic lymphohistiocytosis associated with coccidiomycosis.
BMJ Case Rep. 2014;2014
Authors: Ramsi M, Alvira C, Purohit P, Cornfield D
Haemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal disease caused by dysregulated histiocytes leading to an excessive inflammatory reaction. While genetic forms of HLH exist, the most common form is acquired, frequently associated with infection. Here we report the first case of HLH associated with a coccidiomycosis infection. This patient is a 13-year-old previously healthy boy who presented with a flu-like illness, which rapidly progressed to refractory shock, severe ARDS, multiorgan failure and death despite maximal medical therapy, including broad-spectrum antibiotics to treat well-established causes of acquired HLH. Autopsy findings revealed the diagnosis of HLH in the setting of pulmonary coccidiomycosis. Antifungal therapy should be considered in cases of acquired HLH when the underlying aetiology is not clear.
PMID: 25139924 [PubMed - in process]
Integrative structure-function mapping of the nucleoporin Nup133 suggests a conserved mechanism for membrane anchoring of the nuclear pore complex.
Mol Cell Proteomics. 2014 Aug 19;
Authors: Kim SJ, Fernandez-Martinez J, Sampathkumar P, Martel A, Matsui T, Tsuruta H, Weiss T, Markina-Inarrairaegui A, Bonanno JB, Sauder JM, Burley SK, Almo SC, Rout M, Sali A
The nuclear pore complex (NPC) is the sole passageway for the transport of macromolecules across the nuclear envelope. Nup133, a major component in the Y- shaped Nup84 complex, is an essential scaffold protein of the NPC's outer ring structure. Here, we describe an integrative modeling approach that produces atomic models for multiple states of Saccharomyces cerevisiae (Sc) Nup133, based on the crystal structures of the sequence segments and their homologs including the related Vanderwaltozyma polyspora (Vp) Nup133 residues 55 to 502 (VpNup133(55-502)) determined in this study, small angle X-ray scattering (SAXS) profiles for 18 constructs of ScNup133 and one construct of VpNup133, and 23 negative-stain electron microscopy (EM) class averages of ScNup133(2-1157). Using our integrative approach, we then computed a multi-state structural model of the full-length ScNup133, followed by validation with mutational studies and 45 chemical cross-links determined by mass spectrometry. Finally, the model of ScNup133 allowed us to annotate a potential ArfGAP1 lipid packing sensor (ALPS) motif in Sc and VpNup133 and discuss its potential significance in the context of the whole NPC; we suggest that ALPS motifs are scattered throughout the NPC's scaffold of all eukaryotes and play a major role in the assembly and membrane anchoring of the NPC in the nuclear envelope. Our results are consistent with a common evolutionary origin of Nup133 with membrane coating complexes (the protocoatomer hypothesis); the presence of the ALPS motifs in coatomer-like nucleoporins suggests an ancestral mechanism for membrane recognition present in early membrane coating complexes.
PMID: 25139911 [PubMed - as supplied by publisher]
Coordinating cell polarity: heading in the right direction?
Development. 2014 Sep;141(17):3298-3302
Authors: Axelrod JD, Bergmann DC
A diverse group of researchers working on both plant and animal systems met at a Company of Biologists workshop to discuss 'Coordinating Cell Polarity'. The meeting included considerable free discussion as well as presentations exploring the ways that groups of cells in these various systems achieve coordinated cell polarity. Here, we discuss commonalities, differences and themes that emerged from these sessions that will serve to inform ongoing studies.
PMID: 25139852 [PubMed - as supplied by publisher]
Leveraging Administrative Data for Program Evaluations: A Method for Linking Data Sets Without Unique Identifiers.
Eval Health Prof. 2014 Aug 19;
Authors: Lorden AL, Radcliff TA, Jiang L, Horel SA, Smith ML, Lorig K, Howell BL, Whitelaw N, Ory M
In community-based wellness programs, Social Security Numbers (SSNs) are rarely collected to encourage participation and protect participant privacy. One measure of program effectiveness includes changes in health care utilization. For the 65 and over population, health care utilization is captured in Medicare administrative claims data. Therefore, methods as described in this article for linking participant information to administrative data are useful for program evaluations where unique identifiers such as SSN are not available. Following fuzzy matching methodologies, participant information from the National Study of the Chronic Disease Self-Management Program was linked to Medicare administrative data. Linking variables included participant name, date of birth, gender, address, and ZIP code. Seventy-eight percent of participants were linked to their Medicare claims data. Linking program participant information to Medicare administrative data where unique identifiers are not available provides researchers with the ability to leverage claims data to better understand program effects.
PMID: 25139849 [PubMed - as supplied by publisher]
The brassinosteroid signaling network-a paradigm of signal integration.
Curr Opin Plant Biol. 2014 Aug 12;21C:147-153
Authors: Wang W, Bai MY, Wang ZY
Many hormonal and environmental signals regulate common cellular and developmental processes in plants. While the molecular pathways that transduce these signals have each been studied in detail, how these pathways are wired into regulatory networks to provide the coordinated responses has remained an outstanding question. Recent studies of the brassinosteroid signaling network have revealed extensive signal integration through direct interactions between components of different signaling pathways. In particular, a circuit of interacting transcription regulators integrates many signaling pathways to enable coordinated and coherent regulation of seedling morphogenesis by hormonal and environmental signals. The recent studies support an emerging theme that complex networks of highly integrated signaling pathways underlie the high levels of developmental plasticity and environmental adaptability of plants.
PMID: 25139830 [PubMed - as supplied by publisher]
Authors' reply to de Vries.
Authors: Lund M, Pasternak B, Wohlfahrt J, Melbye M
PMID: 25139721 [PubMed - in process]
Biomaterials for Craniofacial Bone Engineering.
J Dent Res. 2014 Aug 19;
Authors: Tevlin R, McArdle A, Atashroo D, Walmsley GG, Senarath-Yapa K, Zielins ER, Paik KJ, Longaker MT, Wan DC
Conditions such as congenital anomalies, cancers, and trauma can all result in devastating deficits of bone in the craniofacial skeleton. This can lead to significant alteration in function and appearance that may have significant implications for patients. In addition, large bone defects in this area can pose serious clinical dilemmas, which prove difficult to remedy, even with current gold standard surgical treatments. The craniofacial skeleton is complex and serves important functional demands. The necessity to develop new approaches for craniofacial reconstruction arises from the fact that traditional therapeutic modalities, such as autologous bone grafting, present myriad limitations and carry with them the potential for significant complications. While the optimal bone construct for tissue regeneration remains to be elucidated, much progress has been made in the past decade. Advances in tissue engineering have led to innovative scaffold design, complemented by progress in the understanding of stem cell-based therapy and growth factor enhancement of the healing cascade. This review focuses on the role of biomaterials for craniofacial bone engineering, highlighting key advances in scaffold design and development.
PMID: 25139365 [PubMed - as supplied by publisher]
KIR diversity in Māori and Polynesians: populations in which HLA-B is not a significant KIR ligand.
Immunogenetics. 2014 Aug 21;
Authors: Nemat-Gorgani N, Edinur HA, Hollenbach JA, Traherne JA, Dunn PP, Chambers GK, Parham P, Norman PJ
HLA class I molecules and killer cell immunoglobulin-like receptors (KIR) form a diverse system of ligands and receptors that individualize human immune systems in ways that improve the survival of individuals and populations. Human settlement of Oceania by island-hopping East and Southeast Asian migrants started ~3,500 years ago. Subsequently, New Zealand was reached ~750 years ago by ancestral Māori. To examine how this history impacted KIR and HLA diversity, and their functional interaction, we defined at high resolution the allelic and haplotype diversity of the 13 expressed KIR genes in 49 Māori and 34 Polynesians. Eighty KIR variants, including four 'new' alleles, were defined, as were 35 centromeric and 22 telomeric KIR region haplotypes, which combine to give >50 full-length KIR haplotypes. Two new and divergent variant KIR form part of a telomeric KIR haplotype, which appears derived from Papua New Guinea and was probably obtained by the Asian migrants en route to Polynesia. Māori and Polynesian KIR are very similar, but differ significantly from African, European, Japanese, and Amerindian KIR. Māori and Polynesians have high KIR haplotype diversity with corresponding allotype diversity being maintained throughout the KIR locus. Within the population, each individual has a unique combination of HLA class I and KIR. Characterizing Māori and Polynesians is a paucity of HLA-B allotypes recognized by KIR. Compensating for this deficiency are high frequencies (>50 %) of HLA-A allotypes recognized by KIR. These HLA-A allotypes are ones that modern humans likely acquired from archaic humans at a much earlier time.
PMID: 25139336 [PubMed - as supplied by publisher]
More with Less: Pancreas-Preserving Total Duodenectomy.
Dig Dis Sci. 2014 Aug 20;
Authors: Qadan M, Dua M, Worhunsky D, Triadafilopoulos G, Visser B
PMID: 25138905 [PubMed - as supplied by publisher]
Non-MalIg(G4)nant Biliary Obstruction: When the Pill Is Mightier than the Knife.
Dig Dis Sci. 2014 Aug 20;
Authors: Dua MM, Qadan M, Lutchman GA, Park WG, Triadafilopoulos G, Visser BC
PMID: 25138904 [PubMed - as supplied by publisher]
Relationship Among 25-Hydroxyvitamin D Concentrations, Insulin Action, and Cardiovascular Disease Risk in Patients With Essential Hypertension.
Am J Hypertens. 2014 Aug 19;
Authors: Abbasi F, Feldman D, Caulfield MP, Hantash FM, Reaven GM
BACKGROUND: Although low plasma 25-hydroxyvitamin D (25(OH)D) concentrations have been shown to predict risk of hypertension and associated cardiovascular disease (CVD), vitamin D repletion has not consistently lowered blood pressure or decreased CVD. One possibility for this discrepancy is the presence of considerable metabolic heterogeneity in patients with hypertension. To evaluate this possibility, we quantified relationships among insulin resistance, 25(OH)D concentration, and CVD risk factor profile in patients with essential hypertension.
METHODS: Measurements were made of 25(OH)D concentrations, multiple CVD risk factors, and insulin resistance by the steady-state plasma glucose concentration during the insulin suppression test in 140 otherwise healthy patients with essential hypertension.
RESULTS: As a group, the patients were overweight/obese and insulin resistant and had low 25(OH)D concentrations. The more insulin resistant the patients were, the worse the CVD risk profile was. In addition, the most insulin-resistant quartile had significantly lower 25(OH)D concentrations than the most insulin-sensitive quartile (20.3±1.4 vs. 25.8±1.4ng/ml; P = 0.005). In the entire group, 25(OH)D concentration significantly correlated with magnitude of insulin resistance (steady-state plasma glucose concentration; r = -0.20; P = 0.02).
CONCLUSIONS: There was considerable metabolic heterogeneity and substantial difference in magnitude of conventional CVD risk factors in patients with similar degrees of blood pressure elevation. The most insulin-resistant quartile of subjects had the lowest 25(OH)D concentration and the most adverse CVD risk profile, and they may be the subset of patients with essential hypertension most likely to benefit from vitamin D repletion.
PMID: 25138785 [PubMed - as supplied by publisher]
RAPID EVOLUTION OF ADAPTIVE NICHE CONSTRUCTION IN EXPERIMENTAL MICROBIAL POPULATIONS.
Evolution. 2014 Aug 19;
Authors: Callahan BJ, Fukami T, Fisher DS
Many species engage in adaptive niche construction: modification of the local environment that increases the modifying organism's competitive fitness. Adaptive niche construction provides an alternative pathway to higher fitness, shaping the environment rather than conforming to it. Yet, experimental evidence for the evolutionary emergence of adaptive niche construction is lacking, leaving its role in evolution uncertain. Here we report a direct observation of the de novo evolution of adaptive niche construction in populations of the bacteria Pseudomonas fluorescens. In a laboratory experiment, we allowed several bacterial populations to adapt to a novel environment and assessed whether niche construction evolved over time. We found that adaptive niche construction emerged rapidly, within approximately 100 generations, and became ubiquitous after approximately 400 generations. The large fitness effect of this niche construction was dominated by the low fitness of evolved strains in the ancestrally modified environment: evolved niche constructors were highly dependent on their specific environmental modifications. Populations were subjected to frequent resetting of environmental conditions and severe reduction of spatial habitat structure, both of which are thought to make adaptive niche construction difficult to evolve. Our finding that adaptive niche construction nevertheless evolved repeatably suggests that it may play a more important role in evolution than generally thought. This article is protected by copyright. All rights reserved.
PMID: 25138718 [PubMed - as supplied by publisher]
Solvent Effects on Polymer Sorting of Carbon Nanotubes with Applications in Printed Electronics.
Small. 2014 Aug 19;
Authors: Wang H, Hsieh B, Jiménez-Osés G, Liu P, Tassone CJ, Diao Y, Lei T, Houk KN, Bao Z
Regioregular poly(3-alkylthiophene) (P3AT) polymers have been previously reported for the selective, high-yield dispersion of semiconducting single-walled carbon nanotubes (SWCNTs) in toluene. Here, five alternative solvents are investigated, namely, tetrahydrofuran, decalin, tetralin, m-xylene, and o-xylene, for the dispersion of SWCNTs by poly(3-dodecylthiophene) P3DDT. The dispersion yield could be increased to over 40% using decalin or o-xylene as the solvents while maintaining high selectivity towards semiconducting SWCNTs. Molecular dynamics (MD) simulations in explicit solvents are used to explain the improved sorting yield. In addition, a general mechanism is proposed to explain the selective dispersion of semiconducting SWCNTs by conjugated polymers. The possibility to perform selective sorting of semiconducting SWCNTs using various solvents provides a greater diversity of semiconducting SWCNT ink properties, such as boiling point, viscosity, and surface tension as well as toxicity. The efficacy of these new semiconducting SWCNT inks is demonstrated by using the high boiling point and high viscosity solvent tetralin for inkjet-printed transistors, where solvent properties are more compatible with the inkjet printing head and improved droplet formation.
PMID: 25138541 [PubMed - as supplied by publisher]
Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States.
JAMA. 2014 Aug 20;312(7):729-38
Authors: Kwan A, Abraham RS, Currier R, Brower A, Andruszewski K, Abbott JK, Baker M, Ballow M, Bartoshesky LE, Bonilla FA, Brokopp C, Brooks E, Caggana M, Celestin J, Church JA, Comeau AM, Connelly JA, Cowan MJ, Cunningham-Rundles C, Dasu T, Dave N, De La Morena MT, Duffner U, Fong CT, Forbes L, Freedenberg D, Gelfand EW, Hale JE, Hanson IC, Hay BN, Hu D, Infante A, Johnson D, Kapoor N, Kay DM, Kohn DB, Lee R, Lehman H, Lin Z, Lorey F, Abdel-Mageed A, Manning A, McGhee S, Moore TB, Naides SJ, Notarangelo LD, Orange JS, Pai SY, Porteus M, Rodriguez R, Romberg N, Routes J, Ruehle M, Rubenstein A, Saavedra-Matiz CA, Scott G, Scott PM, Secord E, Seroogy C, Shearer WT, Siegel S, Silvers SK, Stiehm ER, Sugerman RW, Sullivan JL, Tanksley S, Tierce ML, Verbsky J, Vogel B, Walker R, Walkovich K, Walter JE, Wasserman RL, Watson MS, Weinberg GA, Weiner LB, Wood H, Yates AB, Puck JM
IMPORTANCE: Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births.
OBJECTIVES: To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments.
DESIGN: Epidemiological and retrospective observational study.
SETTING: Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test.
MAIN OUTCOMES AND MEASURES: Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked.
RESULTS: Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia.
CONCLUSIONS AND RELEVANCE: Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.
PMID: 25138334 [PubMed - in process]
Precise estimates of mutation rate and spectrum in yeast.
Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):E2310-8
Authors: Zhu YO, Siegal ML, Hall DW, Petrov DA
Mutation is the ultimate source of genetic variation. The most direct and unbiased method of studying spontaneous mutations is via mutation accumulation (MA) lines. Until recently, MA experiments were limited by the cost of sequencing and thus provided us with small numbers of mutational events and therefore imprecise estimates of rates and patterns of mutation. We used whole-genome sequencing to identify nearly 1,000 spontaneous mutation events accumulated over ∼311,000 generations in 145 diploid MA lines of the budding yeast Saccharomyces cerevisiae. MA experiments are usually assumed to have negligible levels of selection, but even mild selection will remove strongly deleterious events. We take advantage of such patterns of selection and show that mutation classes such as indels and aneuploidies (especially monosomies) are proportionately much more likely to contribute mutations of large effect. We also provide conservative estimates of indel, aneuploidy, environment-dependent dominant lethal, and recessive lethal mutation rates. To our knowledge, for the first time in yeast MA data, we identified a sufficiently large number of single-nucleotide mutations to measure context-dependent mutation rates and were able to (i) confirm strong AT bias of mutation in yeast driven by high rate of mutations from C/G to T/A and (ii) detect a higher rate of mutation at C/G nucleotides in two specific contexts consistent with cytosine methylation in S. cerevisiae.
PMID: 24847077 [PubMed - indexed for MEDLINE]
Linkage disequilibrium and signatures of positive selection around LINE-1 retrotransposons in the human genome.
Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):8131-6
Authors: Kuhn A, Ong YM, Cheng CY, Wong TY, Quake SR, Burkholder WF
Insertions of the human-specific subfamily of LINE-1 (L1) retrotransposon are highly polymorphic across individuals and can critically influence the human transcriptome. We hypothesized that L1 insertions could represent genetic variants determining important human phenotypic traits, and performed an integrated analysis of L1 elements and single nucleotide polymorphisms (SNPs) in several human populations. We found that a large fraction of L1s were in high linkage disequilibrium with their surrounding genomic regions and that they were well tagged by SNPs. However, L1 variants were only partially captured by SNPs on standard SNP arrays, so that their potential phenotypic impact would be frequently missed by SNP array-based genome-wide association studies. We next identified potential phenotypic effects of L1s by looking for signatures of natural selection linked to L1 insertions; significant extended haplotype homozygosity was detected around several L1 insertions. This finding suggests that some of these L1 insertions may have been the target of recent positive selection.
PMID: 24847061 [PubMed - indexed for MEDLINE]
Wireless power transfer to deep-tissue microimplants.
Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):7974-9
Authors: Ho JS, Yeh AJ, Neofytou E, Kim S, Tanabe Y, Patlolla B, Beygui RE, Poon AS
The ability to implant electronic systems in the human body has led to many medical advances. Progress in semiconductor technology paved the way for devices at the scale of a millimeter or less ("microimplants"), but the miniaturization of the power source remains challenging. Although wireless powering has been demonstrated, energy transfer beyond superficial depths in tissue has so far been limited by large coils (at least a centimeter in diameter) unsuitable for a microimplant. Here, we show that this limitation can be overcome by a method, termed midfield powering, to create a high-energy density region deep in tissue inside of which the power-harvesting structure can be made extremely small. Unlike conventional near-field (inductively coupled) coils, for which coupling is limited by exponential field decay, a patterned metal plate is used to induce spatially confined and adaptive energy transport through propagating modes in tissue. We use this method to power a microimplant (2 mm, 70 mg) capable of closed-chest wireless control of the heart that is orders of magnitude smaller than conventional pacemakers. With exposure levels below human safety thresholds, milliwatt levels of power can be transferred to a deep-tissue (>5 cm) microimplant for both complex electronic function and physiological stimulation. The approach developed here should enable new generations of implantable systems that can be integrated into the body at minimal cost and risk.
PMID: 24843161 [PubMed - indexed for MEDLINE]
Quenched disorder and vestigial nematicity in the pseudogap regime of the cuprates.
Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):7980-5
Authors: Nie L, Tarjus G, Kivelson SA
The cuprate high-temperature superconductors have been the focus of unprecedentedly intense and sustained study not only because of their high superconducting transition temperatures, but also because they represent the most exquisitely investigated examples of highly correlated electronic materials. In particular, the pseudogap regime of the phase diagram exhibits a variety of mysterious emergent behaviors. In the last few years, evidence from NMR and scanning tunneling microscopy (STM) studies, as well as from a new generation of X-ray scattering experiments, has accumulated, indicating that a general tendency to short-range-correlated incommensurate charge density wave (CDW) order is "intertwined" with the superconductivity in this regime. Additionally, transport, STM, neutron-scattering, and optical experiments have produced evidence--not yet entirely understood--of the existence of an associated pattern of long-range-ordered point-group symmetry breaking with an electron-nematic character. We have carried out a theoretical analysis of the Landau-Ginzburg-Wilson effective field theory of a classical incommensurate CDW in the presence of weak quenched disorder. Although the possibilities of a sharp phase transition and long-range CDW order are precluded in such systems, we show that any discrete symmetry-breaking aspect of the charge order--nematicity in the case of the unidirectional (stripe) CDW we consider explicitly--generically survives up to a nonzero critical disorder strength. Such "vestigial order," which is subject to unambiguous macroscopic detection, can serve as an avatar of what would be CDW order in the ideal, zero disorder limit. Various recent experiments in the pseudogap regime of the hole-doped cuprates are readily interpreted in light of these results.
PMID: 24799709 [PubMed - indexed for MEDLINE]
State medicaid coverage, ESRD incidence, and access to care.
J Am Soc Nephrol. 2014 Jun;25(6):1321-9
Authors: Kurella-Tamura M, Goldstein BA, Hall YN, Mitani AA, Winkelmayer WC
The proportion of low-income nonelderly adults covered by Medicaid varies widely by state. We sought to determine whether broader state Medicaid coverage, defined as the proportion of each state's low-income nonelderly adult population covered by Medicaid, associates with lower state-level incidence of ESRD and greater access to care. The main outcomes were incidence of ESRD and five indicators of access to care. We identified 408,535 adults aged 20-64 years, who developed ESRD between January 1, 2001, and December 31, 2008. Medicaid coverage among low-income nonelderly adults ranged from 12.2% to 66.0% (median 32.5%). For each additional 10% of the low-income nonelderly population covered by Medicaid, there was a 1.8% (95% confidence interval, 1.0% to 2.6%) decrease in ESRD incidence. Among nonelderly adults with ESRD, gaps in access to care between those with private insurance and those with Medicaid were narrower in states with broader coverage. For a 50-year-old white woman, the access gap to the kidney transplant waiting list between Medicaid and private insurance decreased by 7.7 percentage points in high (>45%) versus low (<25%) Medicaid coverage states. Similarly, the access gap to transplantation decreased by 4.0 percentage points and the access gap to peritoneal dialysis decreased by 3.8 percentage points in high Medicaid coverage states. In conclusion, states with broader Medicaid coverage had a lower incidence of ESRD and smaller insurance-related access gaps.
PMID: 24652791 [PubMed - indexed for MEDLINE]
Structure of the extended-spectrum class C β-lactamase ADC-1 from Acinetobacter baumannii.
Acta Crystallogr D Biol Crystallogr. 2014 Mar;70(Pt 3):760-71
Authors: Bhattacharya M, Toth M, Antunes NT, Smith CA, Vakulenko SB
ADC-type class C β-lactamases comprise a large group of enzymes that are encoded by genes located on the chromosome of Acinetobacter baumannii, a causative agent of serious bacterial infections. Overexpression of these enzymes renders A. baumannii resistant to various β-lactam antibiotics and thus severely compromises the ability to treat infections caused by this deadly pathogen. Here, the high-resolution crystal structure of ADC-1, the first member of this clinically important family of antibiotic-resistant enzymes, is reported. Unlike the narrow-spectrum class C β-lactamases, ADC-1 is capable of producing resistance to the expanded-spectrum cephalosporins, rendering them inactive against A. baumannii. The extension of the substrate profile of the enzyme is likely to be the result of structural differences in the R2-loop, primarily the deletion of three residues and subsequent rearrangement of the A10a and A10b helices. These structural rearrangements result in the enlargement of the R2 pocket of ADC-1, allowing it to accommodate the bulky R2 substituents of the third-generation cephalosporins, thus enhancing the catalytic efficiency of the enzyme against these clinically important antibiotics.
PMID: 24598745 [PubMed - indexed for MEDLINE]
Reconstructing Native American migrations from whole-genome and whole-exome data.
PLoS Genet. 2013;9(12):e1004023
Authors: Gravel S, Zakharia F, Moreno-Estrada A, Byrnes JK, Muzzio M, Rodriguez-Flores JL, Kenny EE, Gignoux CR, Maples BK, Guiblet W, Dutil J, Via M, Sandoval K, Bedoya G, 1000 Genomes Project, Oleksyk TK, Ruiz-Linares A, Burchard EG, Martinez-Cruzado JC, Bustamante CD
There is great scientific and popular interest in understanding the genetic history of populations in the Americas. We wish to understand when different regions of the continent were inhabited, where settlers came from, and how current inhabitants relate genetically to earlier populations. Recent studies unraveled parts of the genetic history of the continent using genotyping arrays and uniparental markers. The 1000 Genomes Project provides a unique opportunity for improving our understanding of population genetic history by providing over a hundred sequenced low coverage genomes and exomes from Colombian (CLM), Mexican-American (MXL), and Puerto Rican (PUR) populations. Here, we explore the genomic contributions of African, European, and especially Native American ancestry to these populations. Estimated Native American ancestry is 48% in MXL, 25% in CLM, and 13% in PUR. Native American ancestry in PUR is most closely related to populations surrounding the Orinoco River basin, confirming the Southern American ancestry of the Taíno people of the Caribbean. We present new methods to estimate the allele frequencies in the Native American fraction of the populations, and model their distribution using a demographic model for three ancestral Native American populations. These ancestral populations likely split in close succession: the most likely scenario, based on a peopling of the Americas 16 thousand years ago (kya), supports that the MXL Ancestors split 12.2kya, with a subsequent split of the ancestors to CLM and PUR 11.7kya. The model also features effective populations of 62,000 in Mexico, 8,700 in Colombia, and 1,900 in Puerto Rico. Modeling Identity-by-descent (IBD) and ancestry tract length, we show that post-contact populations also differ markedly in their effective sizes and migration patterns, with Puerto Rico showing the smallest effective size and the earlier migration from Europe. Finally, we compare IBD and ancestry assignments to find evidence for relatedness among European founders to the three populations.
PMID: 24385924 [PubMed - indexed for MEDLINE]
Genetic recombination is targeted towards gene promoter regions in dogs.
PLoS Genet. 2013;9(12):e1003984
Authors: Auton A, Rui Li Y, Kidd J, Oliveira K, Nadel J, Holloway JK, Hayward JJ, Cohen PE, Greally JM, Wang J, Bustamante CD, Boyko AR
The identification of the H3K4 trimethylase, PRDM9, as the gene responsible for recombination hotspot localization has provided considerable insight into the mechanisms by which recombination is initiated in mammals. However, uniquely amongst mammals, canids appear to lack a functional version of PRDM9 and may therefore provide a model for understanding recombination that occurs in the absence of PRDM9, and thus how PRDM9 functions to shape the recombination landscape. We have constructed a fine-scale genetic map from patterns of linkage disequilibrium assessed using high-throughput sequence data from 51 free-ranging dogs, Canis lupus familiaris. While broad-scale properties of recombination appear similar to other mammalian species, our fine-scale estimates indicate that canine highly elevated recombination rates are observed in the vicinity of CpG rich regions including gene promoter regions, but show little association with H3K4 trimethylation marks identified in spermatocytes. By comparison to genomic data from the Andean fox, Lycalopex culpaeus, we show that biased gene conversion is a plausible mechanism by which the high CpG content of the dog genome could have occurred.
PMID: 24348265 [PubMed - indexed for MEDLINE]
Evidence that masking of synapsis imperfections counterbalances quality control to promote efficient meiosis.
PLoS Genet. 2013;9(12):e1003963
Authors: Mlynarczyk-Evans S, Roelens B, Villeneuve AM
Reduction in ploidy to generate haploid gametes during sexual reproduction is accomplished by the specialized cell division program of meiosis. Pairing between homologous chromosomes and assembly of the synaptonemal complex at their interface (synapsis) represent intermediate steps in the meiotic program that are essential to form crossover recombination-based linkages between homologs, which in turn enable segregation of the homologs to opposite poles at the meiosis I division. Here, we challenge the mechanisms of pairing and synapsis during C. elegans meiosis by disrupting the normal 1:1 correspondence between homologs through karyotype manipulation. Using a combination of cytological tools, including S-phase labeling to specifically identify X chromosome territories in highly synchronous cohorts of nuclei and 3D rendering to visualize meiotic chromosome structures and organization, our analysis of trisomic (triplo-X) and polyploid meiosis provides insight into the principles governing pairing and synapsis and how the meiotic program is "wired" to maximize successful sexual reproduction. We show that chromosomes sort into homologous groups regardless of chromosome number, then preferentially achieve pairwise synapsis during a period of active chromosome mobilization. Further, comparisons of synapsis configurations in triplo-X germ cells that are proficient or defective for initiating recombination suggest a role for recombination in restricting chromosomal interactions to a pairwise state. Increased numbers of homologs prolong markers of the chromosome mobilization phase and/or boost germline apoptosis, consistent with triggering quality control mechanisms that promote resolution of synapsis problems and/or cull meiocytes containing synapsis defects. However, we also uncover evidence for the existence of mechanisms that "mask" defects, thus allowing resumption of prophase progression and survival of germ cells despite some asynapsis. We propose that coupling of saturable masking mechanisms with stringent quality controls maximizes meiotic success by making progression and survival dependent on achieving a level of synapsis sufficient for crossover formation without requiring perfect synapsis.
PMID: 24339786 [PubMed - indexed for MEDLINE]
Proteome-wide enrichment of proteins modified by lysine methylation.
Nat Protoc. 2014 Jan;9(1):37-50
Authors: Carlson SM, Moore KE, Green EM, Martín GM, Gozani O
We present a protocol for using the triple malignant brain tumor domains of L3MBTL1 (3xMBT), which bind to mono- and di-methylated lysine with minimal sequence specificity, in order to enrich for such methylated lysine from cell lysates. Cells in culture are grown with amino acids containing light or heavy stable isotopic labels. Methylated proteins are enriched by incubating cell lysates with 3xMBT, or with the binding-null D355N mutant as a negative control. Quantitative liquid chromatography and tandem mass spectrometry (LC-MS/MS) are then used to identify proteins that are specifically enriched by 3xMBT pull-down. The addition of a third isotopic label allows the comparison of protein lysine methylation between different biological conditions. Unlike most approaches, our strategy does not require a prior hypothesis of candidate methylated proteins, and it recognizes a wider range of methylated proteins than any available method using antibodies. Cells are prepared by growing in isotopic labeling medium for about 7 d; the process of enriching methylated proteins takes 3 d and analysis by LC-MS/MS takes another 1-2 d.
PMID: 24309976 [PubMed - indexed for MEDLINE]
Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy.
Eur Urol. 2014 Mar;65(3):577-84
Authors: McKay RR, Kroeger N, Xie W, Lee JL, Knox JJ, Bjarnason GA, MacKenzie MJ, Wood L, Srinivas S, Vaishampayan UN, Rha SY, Pal SK, Donskov F, Tantravahi SK, Rini BI, Heng DY, Choueiri TK
BACKGROUND: The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC).
OBJECTIVE: To analyze outcomes based on the presence of bone metastases (BMs) and/or liver metastases (LMs) in patients with RCC treated with targeted therapy.
DESIGN, SETTING, AND PARTICIPANTS: We conducted a review from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 2027 patients with metastatic RCC.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed the impact of the site of metastasis on overall survival (OS) and time-to-treatment failure. Statistical analyses were performed using multivariable Cox regression.
RESULTS AND LIMITATIONS: The presence of BMs was 34% overall, and when stratified by IMDC risk groups was 27%, 33%, and 43% in the favorable-, intermediate-, and poor-risk groups, respectively (p<0.001). The presence of LMs was 19% overall and higher in the poor-risk patients (23%) compared with the favorable- or intermediate-risk groups (17%) (p=0.003). When patients were classified into four groups based on the presence of BMs and/or LMs, the hazard ratio, adjusted for IMDC risk factors, was 1.4 (95% confidence interval [CI], 1.22-1.62) for BMs, 1.42 (95% CI, 1.17-1.73) for LMs, and 1.82 (95% CI, 1.47-2.26) for both BMs and LMs compared with other metastatic sites (p<0.0001). The prediction model performance for OS was significantly improved when BMs and LMs were added to the IMDC prognostic model (likelihood ratio test p<0.0001). Data in this analysis were collected retrospectively.
CONCLUSIONS: The presence of BMs and LMs in patients treated with targeted agents has a negative impact on survival. Patients with BMs and/or LMs may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.
PMID: 23962746 [PubMed - indexed for MEDLINE]
The effect of pedicle screw redirection after lateral wall breach--a biomechanical study using human lumbar vertebrae.
Spine J. 2014 Jan;14(1):98-103
Authors: Stauff MP, Freedman BA, Kim JH, Hamasaki T, Yoon ST, Hutton WC
BACKGROUND CONTEXT: Currently, pedicle screw segmental fixation of the spine is considered a standard of care for a number of conditions. Most surgeons employ a free-hand technique using various intraoperative modalities to improve pedicle screw accuracy. Despite continued improvements in technique, pedicle breach remains a frequent occurrence. Once a breach is detected intraoperatively, the most common corrective maneuver is to medially redirect the pedicle screw into the pedicle. To our knowledge, the biomechanical impact of medially redirecting a pedicle screw after a lateral pedicle breach has not been examined.
PURPOSE: To compare the fixation strength of perfectly placed pedicle screws to the fixation strength of pedicle screws that were correctly placed after having been redirected (RD) following a lateral pedicle breach.
STUDY DESIGN/SETTING: A biomechanical study using human lumbar vertebrae.
METHODS: Ten fresh human lumbar vertebrae were isolated from five donors. Each vertebra was instrumented with a monoaxial pedicle screw into each pedicle using two different techniques. On one side, a perfect center-center (CC) screw path was created using direct visualization and fluoroscopy. A 6.0-mm-diameter cannulated tap and a pedicle probe were used to develop the pedicle for the 7.0-mm-diameter by 45-mm-long cannulated pedicle screw, which was placed using a digital torque driver. On the contralateral side, an intentional lateral pedicle wall breach was created at the pedicle-vertebral body junction using a guide wire, a 6.0-mm-diameter cannulated tap, and a pedicle probe. This path was then redirected into a CC position, developed, and instrumented with a 7.0-mm-diameter by 45-mm-long cannulated pedicle screw: the RD screw. For each pedicle screw, we assessed four outcome measures: maximal torque, seating torque, screw loosening, and post-loosening axial pullout. Screw loosening and axial pullout were assessed using an MTS machine.
RESULTS: The biomechanical cost of a lateral pedicle breach and the requirement to redirect the pedicle screw are as follows: an overall drop of 28% (p<.002) in maximal insertion torque and 25% (p<.049) in seating torque, a drop of 25% (p<.040) in resistance to screw loosening, and a drop in axial pullout force of 11% (p<.047).
CONCLUSIONS: Compared with a CC lumbar pedicle screw, an RD lumbar pedicle screw placed after a lateral wall breach is significantly weaker in terms of maximal insertional torque, seating torque, screw loosening force, and axial pullout strength. These significant decreases in biomechanical properties are clearly important when RD pedicle screws are placed at the cephalad or caudal end of a long construct. In this situation, augmentation of the RD screw is an option.
PMID: 23623630 [PubMed - indexed for MEDLINE]
Detectable prostate-specific antigen Nadir during androgen-deprivation therapy predicts adverse prostate cancer-specific outcomes: results from the SEARCH database.
Eur Urol. 2014 Mar;65(3):620-7
Authors: Keto CJ, Aronson WJ, Terris MK, Presti JC, Kane CJ, Amling CL, Freedland SJ
BACKGROUND: A prostate-specific antigen (PSA) level <0.2 ng/ml 8 mo after starting on androgen-deprivation therapy (ADT) is correlated with better outcomes. However, not all men reach a nadir PSA level within 8 mo. Whether the lowest PSA on ADT-specifically, <0.2 ng/ml-can be used for risk stratification is untested.
OBJECTIVE: We examined the predictive value of small but detectable PSA nadir values on prostate cancer (PCa)-specific outcomes in men treated with early ADT after radical prostatectomy (RP).
DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective review of men treated with ADT after RP before metastases from the SEARCH database. We identified 402 men treated with ADT for elevated PSA following RP, of whom 294 men had complete data. Median follow-up after PSA nadir was 49 mo. All men had a PSA nadir <4 ng/ml; 223 men (76%) had an undetectable nadir.
INTERVENTION: ADT for an elevated PSA following RP with no radiographic evidence of metastatic disease.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA nadir on ADT was defined as the lowest PSA value during ADT. Proportional hazards models and the C index were used to test the association and predictive accuracy, respectively, between PSA nadir and PCa-specific outcomes.
RESULTS AND LIMITATIONS: Men with a PSA nadir between 0.01 and 0.2 ng/ml had a greater risk of progression to castration-resistant PCa (CRPC) (hazard ratio [HR]: 5.14; p<0.001), metastases (HR: 3.98; p=0.006), and PCa-specific mortality (PCSM) (HR: 5.33; p=0.003) than men with an undetectable nadir. When data were restricted to men followed with ultrasensitive PSA values (sensitivity of 0.01 ng/ml), the C index of PSA nadir alone for predicting CRPC, metastases, and PCSM was 0.88, 0.91, and 0.96, respectively.
CONCLUSIONS: A PSA nadir on ADT, even at a very low level, strongly predicts progression to CRPC, metastases, and PCSM. Men with a detectable PSA nadir during ADT should be considered for clinical trials.
PMID: 23245686 [PubMed - indexed for MEDLINE]
Impact of bone morphogenetic proteins on frequency of revision surgery, use of autograft bone, and total hospital charges in surgery for lumbar degenerative disease: review of the Nationwide Inpatient Sample from 2002 to 2008.
Spine J. 2014 Jan;14(1):20-30
Authors: Dagostino PR, Whitmore RG, Smith GA, Maltenfort MG, Ratliff JK
BACKGROUND CONTEXT: Bone morphogenetic proteins (BMPs) were developed with the goal of improving clinical outcomes through the promotion of bony healing and reducing morbidity from iliac crest bone graft harvest.
PURPOSE: To complete a population-based assessment of the impact of BMP on use of autograft, rates of operative treatment for lumbar pseudoarthrosis, and hospital charges.
STUDY DESIGN: Nationwide Inpatient Sample (NIS) retrospective cohort assessment of 46,452 patients from 2002 to 2008.
PATIENT SAMPLE: All patients who underwent lumbar arthrodesis procedures for degenerative spinal disease.
OUTCOME MEASURES: Use of BMP, revision surgery status as a percentage of total procedures, and autograft harvest in lumbar fusion procedures completed for degenerative diagnoses.
METHODS: Demographic and geographic/practice data, hospital charges, and length of stay of all NIS patients with thoracolumbar and lumbosacral procedure codes for degenerative spinal diagnoses were recorded. Codes for autograft harvest, use of BMP, and revision surgery were included in multivariable regression analysis.
RESULTS: The assessment found 46,452 patients from 2002 to 2008 undergoing thoracolumbar or lumbar arthrodesis procedures for degenerative disease. Assuming a representative sample, this cohort models more than 200,000 US patients. There was steady growth in lumbar spine fusion and in the use of BMP. The use of BMP increased from 2002 to 2008 (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.48-1.52). Revision procedures decreased over the study period (OR, 0.94; 95% CI, 0.91-0.96). The use of autograft decreased substantially after introduction of BMP but then returned to baseline levels; there was no net change in autograft use from 2002 to 2008. The use of BMP correlated with significant increases in hospital charges ($13,362.39; standard deviation ± 596.28, p<.00001). The use of BMP in degenerative thoracolumbar procedures potentially added more than $900 million to hospital charges from 2002 to 2008.
CONCLUSIONS: There was an overall decrease in rates of revision fusion procedures from 2002 to 2008. Introduction of BMP did not correlate with decrease in use of autograft bone harvest. Use of BMP correlated with substantial increase in hospital charges. The small decrease in revision surgeries recorded, combined with lack of significant change in autograft harvest rates, may question the financial justification for the use of BMP.
PMID: 23218827 [PubMed - indexed for MEDLINE]
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