The metabolic enzyme CTP synthase forms cytoskeletal filaments

Filament-forming cytoskeletal proteins are essential for the structure and organization of all cells. Bacterial homologues of the major eukaryotic cytoskeletal families have now been discovered, but studies suggest that yet more remain to be identified. We demonstrate that the metabolic enzyme CTP synthase (CtpS) forms filaments in Caulobacter crescentus. CtpS is bifunctional, as the filaments it forms regulate the curvature of C. crescentus cells independently of its catalytic function. The morphogenic role of CtpS requires its functional interaction with the intermediate filament, crescentin (CreS). Interestingly, the Escherichia coli CtpS homologue also forms filaments both in vivo and in vitro, suggesting that CtpS polymerization may be widely conserved. E. coli CtpS can replace the enzymatic and morphogenic functions of C. crescentus CtpS, indicating that C. crescentus has adapted a conserved filament-forming protein for a secondary role. These results implicate CtpS as a novel bifunctional member of the bacterial cytoskeleton and suggest that localization and polymerization may be important properties of metabolic enzymes

Far Infrared Prperties of M Dwarfs

We report the mid- and far-infrared properties of nearby M dwarfs. Spitzer/MIPS measurements were obtained for a sample of 62 stars at 24 um, with subsamples of 41 and 20 stars observed at 70 um and 160 um respectively. We compare the results with current models of M star photospheres and look for indications of circumstellar dust in the form of significant deviations of K-[24 um] colors and 70 um / 24 um flux ratios from the average M star values. At 24 um, all 62 of the targets were detected; 70 um detections were achieved for 20 targets in the subsample observed; and no detections were seen in the 160 um subsample. No clear far-infrared excesses were detected in our sample. The average far infrared excess relative to the photospheric emission of the M stars is at least four times smaller than the similar average for a sample of solar-type stars. However, this limit allows the average fractional infrared luminosity in the M-star sample to be similar to that for more massive stars. We have also set low limits for the maximum mass of dust possible around our stars.Comment: 28 pages, 4 figures, to be published in The Astrophysical Journa

Sleep problems for children with autism and caregiver spillover effects

Sleep problems in children with autism spectrum disorders (ASD) are under-recognized and under-treated. Identifying treatment value accounting for health effects on family members (spillovers) could improve the perceived cost-effectiveness of interventions to improve child sleep habits. A prospective cohort study (N = 224) was conducted with registry and postal survey data completed by the primary caregiver.Wecalculated quality of life outcomes for the child and the primary caregiver associated with treatments to improve sleep in the child based on prior clinical trials. Predicted treatment effects for melatonin and behavioral interventions were similar in magnitude for the child and for the caregiver. Accounting for caregiver spillover effects associated with treatments for the child with ASD increases treatment benefits and improves cost-effectiveness profiles

Surface Curvature Differentially Regulates Stem Cell Migration and Differentiation via Altered Attachment Morphology and Nuclear Deformation

Signals from the microenvironment around a cell are known to influence cell behavior. Material properties, such as biochemical composition and substrate stiffness, are today accepted as significant regulators of stem cell fate. The knowledge of how cell behavior is influenced by 3D geometric cues is, however, strongly limited despite its potential relevance for the understanding of tissue regenerative processes and the design of biomaterials. Here, the role of surface curvature on the migratory and differentiation behavior of human mesenchymal stem cells (hMSCs) has been investigated on 3D surfaces with well-defined geometric features produced by stereolithography. Time lapse microscopy reveals a significant increase of cell migration speed on concave spherical compared to convex spherical structures and flat surfaces resulting from an upward-lift of the cell body due to cytoskeletal forces. On convex surfaces, cytoskeletal forces lead to substantial nuclear deformation, increase lamin-A levels and promote osteogenic differentiation. The findings of this study demonstrate a so far missing link between 3D surface curvature and hMSC behavior. This will not only help to better understand the role of extracellular matrix architecture in health and disease but also give new insights in how 3D geometries can be used as a cell-instructive material parameter in the field of biomaterial-guided tissue regeneration.Peer reviewe

Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells.

Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments

Infrared Properties of a Complete Sample of Star-Forming Dwarf Galaxies

We present a study of a large, statistically complete sample of star-forming dwarf galaxies using mid-infrared observations from the {\it Spitzer Space Telescope}. The relationships between metallicity, star formation rate (SFR) and mid-infrared color in these systems show that the galaxies span a wide range of properties. However, the galaxies do show a deficit of 8.0 \um\ polycyclic aromatic hydrocarbon emission as is apparent from the median 8.0 \um\ luminosity which is only 0.004 \lstarf\ while the median $B$-band luminosity is 0.05 \lstarb. Despite many of the galaxies being 8.0 \um\ deficient, there is about a factor of 4 more extremely red galaxies in the [3.6] $-$ [8.0] color than for a sample of normal galaxies with similar optical colors. We show correlations between the [3.6] $-$ [8.0] color and luminosity, metallicity, and to a lesser extent SFRs that were not evident in the original, smaller sample studied previously. The luminosity--metallicity relation has a flatter slope for dwarf galaxies as has been indicated by previous work. We also show a relationship between the 8.0 \um\ luminosity and the metallicity of the galaxy which is not expected given the competing effects (stellar mass, stellar population age, and the hardness of the radiation field) that influence the 8.0 \um\ emission. This larger sample plus a well-defined selection function also allows us to compute the 8.0 \um\ luminosity function and compare it with the one for the local galaxy population. Our results show that below 10$^{9}$ $L$\solar, nearly all the 8.0 \um\ luminosity density of the local universe arises from dwarf galaxies that exhibit strong \ha\ emission -- i.e., 8.0 \um\ and \ha\ selection identify similar galaxy populations despite the deficit of 8.0 \um\ emission observed in these dwarfs.Comment: 13 pages, 11 figures, Published in Ap

EFFICACY OF ALIROCUMAB IN 1,191 PATIENTS WITH A WIDE SPECTRUM OF MUTATIONS IN GENES CAUSATIVE FOR FAMILIAL HYPERCHOLESTEROLEMIA

Background Mutation(s) in genes involved in the low-density lipoprotein receptor (LDLR) pathway are typically the underlying cause of familial hypercholesterolemia. Objective The objective of the study was to examine the influence of genotype on treatment responses with alirocumab. Methods Patients from 6 trials (n = 1191, including 758 alirocumab-treated; Clinicaltrials.gov identifiers: NCT01266876; NCT01507831; NCT01623115; NCT01709500; NCT01617655; NCT01709513) were sequenced for mutations in LDLR , apolipoprotein B ( APOB ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), LDLR adaptor protein 1, and signal-transducing adaptor protein 1 genes. New mutations were confirmed by Sanger sequencing. Results One or more specific gene mutations were found in 898 patients (75%): 387 and 437 patients had heterozygous LDLR defective and negative mutations, respectively; 46 had a heterozygous APOB -defective mutation; 8 patients had a heterozygous PCSK9 gain-of-function mutation; 293 (25%) had no identifiable mutation in the genes investigated. LDL cholesterol reductions at Week 24 were generally similar across genotypes: 48.3% (n = 131) and 54.3% (n = 89) in LDLR -defective heterozygotes with alirocumab 75 mg Q2W (with possible increase to 150 mg at Week 12) and 150 mg Q2W, respectively; 49.7% (n = 168) and 60.7% (n = 88) in LDLR -negative heterozygotes; 54.1% (n = 20) and 50.1% (n = 6) in APOB -defective heterozygotes; 60.5% (n = 5) and 94.0% (n = 1) in PCSK9 heterozygotes; and 44.9% (n = 85) and 55.4% (n = 69) in patients with no identified mutations. Overall rates of treatment-emergent adverse events were similar for alirocumab vs controls (placebo in 5 trials, ezetimibe control or atorvastatin calibrator arm in 1 trial), with only a higher rate of injection-site reactions with alirocumab. Conclusions In this large patient cohort, individuals with a wide spectrum of mutations in genes underlying familial hypercholesterolemia responded substantially and similarly to alirocumab treatment

Quantum Cloning and Distributed Measurements

We study measurements on various subsystems of the output of a universal 1 to 2 cloning machine, and establish a correspondence between these measurements at the output and effective measurements on the original input. We show that one can implement sharp effective measurement elements by measuring only two out of the three output systems. Additionally, certain complete sets of sharp measurements on the input can be realised by measurements on the two clones. Furthermore, we introduce a scheme that allows to restore the original input in one of the output bits, by using measurements and classical communication -- a protocol that resembles teleportation.Comment: submitted to Phys. Rev.

Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia

Background Mutations in the genes for the low-density lipoprotein receptor ( LDLR ), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). Objective The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. Methods Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR , apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 ( LDLRAP1 ), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. Results Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39–114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10–165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. Conclusion Clinically meaningful LDL-C–lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH

Financial sector and economic growth in the Republic of Croatia 1995-2005

Financial sector in the Republic of Croatia had a strong growth between 1995 2005.g. Liberalization of financial sector in 1999 led to an increase in bank foreign debt, which resulted in a strong increase in foreign currency reserves and appreciation of the national currency. The growth of the financial sector and credit expansion have been allocated in favour of private and public consumption, but not in industry investments. GDP growth didn't have the same momentum as financial aggregates. Economic growth, after a contraction in 1999 was within the average of global economic growth. Relying on neoclassical growth model, government and central bank didn't put in place the needed set of pro-active policies. Factor allocation was solely through private bank channels financing private consumption. If the sustainable economic growth and new employment are to be major macroeconomic goals, a new macroeconomic paradigm as combination of neclassical and neokeynesians approach will be needed