69 research outputs found
Nrt1 and Tna1-Independent Export of NAD+ Precursor Vitamins Promotes NAD+ Homeostasis and Allows Engineering of Vitamin Production
NAD+ is both a co-enzyme for hydride transfer enzymes and a
substrate of sirtuins and other NAD+ consuming enzymes.
NAD+ biosynthesis is required for two different regimens
that extend lifespan in yeast. NAD+ is synthesized from
tryptophan and the three vitamin precursors of NAD+: nicotinic
acid, nicotinamide and nicotinamide riboside. Supplementation of yeast cells
with NAD+ precursors increases intracellular
NAD+ levels and extends replicative lifespan. Here we show
that both nicotinamide riboside and nicotinic acid are not only vitamins but are
also exported metabolites. We found that the deletion of the nicotinamide
riboside transporter, Nrt1, leads to increased export of nicotinamide riboside.
This discovery was exploited to engineer a strain to produce high levels of
extracellular nicotinamide riboside, which was recovered in purified form. We
further demonstrate that extracellular nicotinamide is readily converted to
extracellular nicotinic acid in a manner that requires intracellular
nicotinamidase activity. Like nicotinamide riboside, export of nicotinic acid is
elevated by the deletion of the nicotinic acid transporter, Tna1. The data
indicate that NAD+ metabolism has a critical extracellular
element in the yeast system and suggest that cells regulate intracellular
NAD+ metabolism by balancing import and export of
NAD+ precursor vitamins
Observation of Orbitally Excited B_s Mesons
We report the first observation of two narrow resonances consistent with
states of orbitally excited (L=1) B_s mesons using 1 fb^{-1} of ppbar
collisions at sqrt{s} = 1.96 TeV collected with the CDF II detector at the
Fermilab Tevatron. We use two-body decays into K^- and B^+ mesons reconstructed
as B^+ \to J/\psi K^+, J/\psi \to \mu^+ \mu^- or B^+ \to \bar{D}^0 \pi^+,
\bar{D}^0 \to K^+ \pi^-. We deduce the masses of the two states to be m(B_{s1})
= 5829.4 +- 0.7 MeV/c^2 and m(B_{s2}^*) = 5839.7 +- 0.7 MeV/c^2.Comment: Version accepted and published by Phys. Rev. Let
Measurement of in Collisions at TeV
We present the first observation of the baryon decay
followed by in 106 pb-1
of collisions at TeV in the CDF experiment. In
order to reduce systematic error, the measured rate for decay is
normalized to the kinematically similar meson decay followed
by . We report the ratio of production cross sections
() times the ratio of branching fractions (BR) for the momentum region
integrated above GeV/c and pseudorapidity range :
.Comment: Submitted to Phys.Rev.Let
Transcriptional Profiling of Chondrodysplasia Growth Plate Cartilage Reveals Adaptive ER-Stress Networks That Allow Survival but Disrupt Hypertrophy
Metaphyseal chondrodysplasia, Schmid type (MCDS) is characterized by mild short stature and growth plate hypertrophic zone expansion, and caused by collagen X mutations. We recently demonstrated the central importance of ER stress in the pathology of MCDS by recapitulating the disease phenotype by expressing misfolding forms of collagen X (Schmid) or thyroglobulin (Cog) in the hypertrophic zone. Here we characterize the Schmid and Cog ER stress signaling networks by transcriptional profiling of microdissected mutant and wildtype hypertrophic zones. Both models displayed similar unfolded protein responses (UPRs), involving activation of canonical ER stress sensors and upregulation of their downstream targets, including molecular chaperones, foldases, and ER-associated degradation machinery. Also upregulated were the emerging UPR regulators Wfs1 and Syvn1, recently identified UPR components including Armet and Creld2, and genes not previously implicated in ER stress such as Steap1 and Fgf21. Despite upregulation of the Chop/Cebpb pathway, apoptosis was not increased in mutant hypertrophic zones. Ultrastructural analysis of mutant growth plates revealed ER stress and disrupted chondrocyte maturation throughout mutant hypertrophic zones. This disruption was defined by profiling the expression of wildtype growth plate zone gene signatures in the mutant hypertrophic zones. Hypertrophic zone gene upregulation and proliferative zone gene downregulation were both inhibited in Schmid hypertrophic zones, resulting in the persistence of a proliferative chondrocyte-like expression profile in ER-stressed Schmid chondrocytes. Our findings provide a transcriptional map of two chondrocyte UPR gene networks in vivo, and define the consequences of UPR activation for the adaptation, differentiation, and survival of chondrocytes experiencing ER stress during hypertrophy. Thus they provide important insights into ER stress signaling and its impact on cartilage pathophysiology
The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review.
BACKGROUND: The management of articular cartilage defects presents many clinical challenges due to its avascular, aneural and alymphatic nature. Bone marrow stimulation techniques, such as microfracture, are the most frequently used method in clinical practice however the resulting mixed fibrocartilage tissue which is inferior to native hyaline cartilage. Other methods have shown promise but are far from perfect. There is an unmet need and growing interest in regenerative medicine and tissue engineering to improve the outcome for patients requiring cartilage repair. Many published reviews on cartilage repair only list human clinical trials, underestimating the wealth of basic sciences and animal studies that are precursors to future research. We therefore set out to perform a systematic review of the literature to assess the translation of stem cell therapy to explore what research had been carried out at each of the stages of translation from bench-top (in vitro), animal (pre-clinical) and human studies (clinical) and assemble an evidence-based cascade for the responsible introduction of stem cell therapy for cartilage defects. This review was conducted in accordance to PRISMA guidelines using CINHAL, MEDLINE, EMBASE, Scopus and Web of Knowledge databases from 1st January 1900 to 30th June 2015. In total, there were 2880 studies identified of which 252 studies were included for analysis (100 articles for in vitro studies, 111 studies for animal studies; and 31 studies for human studies). There was a huge variance in cell source in pre-clinical studies both of terms of animal used, location of harvest (fat, marrow, blood or synovium) and allogeneicity. The use of scaffolds, growth factors, number of cell passages and number of cells used was hugely heterogeneous. SHORT CONCLUSIONS: This review offers a comprehensive assessment of the evidence behind the translation of basic science to the clinical practice of cartilage repair. It has revealed a lack of connectivity between the in vitro, pre-clinical and human data and a patchwork quilt of synergistic evidence. Drivers for progress in this space are largely driven by patient demand, surgeon inquisition and a regulatory framework that is learning at the same pace as new developments take place
Search for chargino-neutralino production in ppbar collisions at sqrt(s) = 1.96 TeV
We present the results of a search for associated production of the chargino
and neutralino supersymmetric particles using up to 1.1 fb-1 of integrated
luminosity collected by the CDF II experiment at the Tevatron ppbar collider at
a center-of-mass energy of 1.96 TeV. The search is conducted by analyzing
events with a large transverse momentum imbalance and either three charged
leptons or two charged leptons of the same electric charge. The numbers of
observed events are found to be consistent with standard model expectations.
Upper limits on the production cross section are derived in different
theoretical models. In one of these models a lower limit on the mass of the
chargino is set at 129 GeV/c^2 at the 95% confidence level.Comment: To be submitted to Phys.Rev.Let
Measurement of the ttbar Production Cross Section in ppbar collisions at sqrt s = 1.96 TeV in the All Hadronic Decay Mode
We report a measurement of the ttbar production cross section using the
CDF-II detector at the Fermilab Tevatron. The analysis is performed using 311
pb-1 of ppbar collisions at sqrt(s)=1.96 TeV. The data consist of events
selected with six or more hadronic jets with additional kinematic requirements.
At least one of these jets must be identified as a b-quark jet by the
reconstruction of a secondary vertex. The cross section is measured to be
sigma(tbart)=7.5+-2.1(stat.)+3.3-2.2(syst.)+0.5-0.4(lumi.) pb, which is
consistent with the standard model prediction.Comment: By CDF collaboratio
The genetic architecture of the human cerebral cortex
The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder
Genetic association study of childhood aggression across raters, instruments, and age
Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis AGGoverall was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations rg among rater-specific assessment of AGG ranged from rg= 0.46 between self- and teacher-assessment to rg= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg|: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg=∼-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.</p
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