Structure and substrate selectivity of the 750-kDa α6β6 holoenzyme of geranyl-CoA carboxylase.

Geranyl-CoA carboxylase (GCC) is essential for the growth of Pseudomonas organisms with geranic acid as the sole carbon source. GCC has the same domain organization and shares strong sequence conservation with the related biotin-dependent carboxylases 3-methylcrotonyl-CoA carboxylase (MCC) and propionyl-CoA carboxylase (PCC). Here we report the crystal structure of the 750-kDa α6β6 holoenzyme of GCC, which is similar to MCC but strikingly different from PCC. The structures provide evidence in support of two distinct lineages of biotin-dependent acyl-CoA carboxylases, one carboxylating the α carbon of a saturated organic acid and the other carboxylating the γ carbon of an α-β unsaturated acid. Structural differences in the active site region of GCC and MCC explain their distinct substrate preferences. Especially, a glycine residue in GCC is replaced by phenylalanine in MCC, which blocks access by the larger geranyl-CoA substrate. Mutation of this residue in the two enzymes can change their substrate preferences

An Unfinished Canvas: Allocating Funding and Instructional Time for Elementary Arts Education

An Unfinished Canvas found that California's elementary schools face unique challenges inproviding all students with sequential, standards-based arts education. In particular, elementary principals identified inadequate funding and insufficient instructional time as significant barriers to the provision of arts education. For this study, we sought to further understand the impact of funding and time on elementary arts education. To do so, we examined the allocation of funding and instructional time in 10 schools across five states (Kentucky, Massachusetts, Minnesota, New Jersey, and California)

An Unfinished Canvas: Arts Education in California: Taking Stock of Policies and Practices

Provides an overview of K-12 arts education, including course offerings; availability of teachers, facilities, and materials; standards alignment, assessment, and accountability practices; and equal access. Discusses barriers and recommendations

An early nimravid from California and the rise of hypercarnivorous mammals after the Middle Eocene Climatic Optimum

Carnivoraforms (crown carnivorans and their closest relatives) first occupied hypercarnivorous niches near the dawn of the late Eocene, 40–37 million years ago. This followed the decline or extinction of earlier carnivorous groups, Mesonychia and Oxyaenodonta, leaving carnivoraforms and hyaenodontan meat-eaters as high trophic level consumers. The pattern of this change and the relative contributions of the taxonomic groups has hitherto been unclear. We report a new genus and species of the sabretoothed mammalian carnivore family Nimravidae, Pangurban egiae, from the Eocene Pomerado Conglomerate of southern California, with strongly derived hypercarnivorous features. While geochronologically the oldest named nimravid in North America, Pangurban egiae is recovered as phylogenetically derived, with affinities to Hoplophoneus. This provides unequivocal evidence for rapid radiation and spread of nimravid carnivores across Asia and North America and constrains the timing of early divergences within the family. Pangurban egiae narrows the gap between convergent iterations of sabretoothed mammalian carnivores and demonstrates swift diversification of the hypercarnivorous nimravids during a period of global climatic instability. Furthermore, it highlights the top-to-bottom restructuring North American ecosystems underwent during the Eocene–Oligocene transition, resulting in carnivoraforms taking positions as trophic specialists for the first time, a niche they still occupy today

Dynamical approach to the jamming problem

A simple dynamical model, Biased Random Organization, BRO, appears to produce configurations known as Random Close Packing (RCP) as BRO's densest critical point in dimension $d=3$. We conjecture that BRO likewise produces RCP in any dimension; if so, then RCP does not exist in $d=1-2$ (where BRO dynamics lead to crystalline order). In $d=3-5$, BRO produces isostatic configurations and previously estimated RCP volume fractions 0.64, 0.46, and 0.30, respectively. For all investigated dimensions ($d=2-5$), we find that BRO belongs to the Manna universality class of dynamical phase transitions by measuring critical exponents associated with the steady-state activity and the long-range density fluctuations. Additionally, BRO's distribution of near-contacts (gaps) displays behavior consistent with the infinite-dimensional theoretical treatment of RCP when $d \ge 4$. The association of BRO's densest critical configurations with Random Close Packing implies that RCP's upper-critical dimension is consistent with the Manna class $d_{uc} = 4$

Age/disease duration influence on activities of daily living and quality of life after levodopa-carbidopa intestinal gel in Parkinson's disease

Aim: To determine if age and Parkinson's disease duration at therapy initiation influence the efficacy of levodopa-carbidopa intestinal gel (LCIG) on quality of life and activities of daily living. Patients & methods: This post hoc analysis assessed subgroups of patients stratified by baseline age, disease duration, hours/day of 'off' time and levodopa equivalent dose. Patients' data were collected from the GLORIA study, a 24-month observational registry evaluating long-term effectiveness of LCIG. Results & conclusion: LCIG therapy led to sustained improvements in quality of life irrespective of patient age and disease duration at baseline. Improvements in activities of daily living were observed across all subgroups, particularly in younger patients, patients with shorter disease duration and in patients with the highest baseline levodopa equivalent dose

Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison.

BACKGROUND: Artemisinin-based combinations are judged the best treatments for multidrug-resistant Plasmodium falciparum malaria. Artesunate-mefloquine is widely recommended in southeast Asia, but its high cost and tolerability profile remain obstacles to widespread deployment. To assess whether dihydroartemisinin-piperaquine is a suitable alternative to artesunate-mefloquine, we compared the safety, tolerability, efficacy, and effectiveness of the two regimens for the treatment of uncomplicated falciparum in western Myanmar (Burma). METHODS: We did an open randomised comparison of 3-day regimens of artesunate-mefloquine (12/25 mg/kg) versus dihydroartemisinin-piperaquine (6.3/50 mg/kg) for the treatment of children aged 1 year or older and in adults with uncomplicated falciparum malaria in Rakhine State, western Myanmar. Within each group, patients were randomly assigned supervised or non-supervised treatment. The primary endpoint was the PCR-confirmed parasitological failure rate by day 42. Failure rates at day 42 were estimated by Kaplan-Meier survival analysis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN27914471. FINDINGS: Of 652 patients enrolled, 327 were assigned dihydroartemisinin-piperaquine (156 supervised and 171 not supervised), and 325 artesunate-mefloquine (162 and 163, respectively). 16 patients were lost to follow-up, and one patient died 22 days after receiving dihydroartemisinin-piperaquine. Recrudescent parasitaemias were confirmed in only two patients; the day 42 failure rate was 0.6% (95% CI 0.2-2.5) for dihydroartemisinin-piperaquine and 0 (0-1.2) for artesunate-mefloquine. Whole-blood piperaquine concentrations at day 7 were similar for patients with observed and non-observed dihydroartemisinin-piperaquine treatment. Gametocytaemia developed more frequently in patients who had received dihydroartemisinin-piperaquine than in those on artesunate-mefloquine: day 7, 18 (10%) of 188 versus five (2%) of 218; relative risk 4.2 (1.6-11.0) p=0.011. INTERPRETATION: Dihydroartemisinin-piperaquine is a highly efficacious and inexpensive treatment of multidrug-resistant falciparum malaria and is well tolerated by all age groups. The effectiveness of the unsupervised treatment, as in the usual context of use, equalled its supervised efficacy, indicating good adherence without supervision. Dihydroartemisinin-piperaquine is a good alternative to artesunate-mefloquine

The Impact of Sleep Debt on Excess Adiposity and Insulin Sensitivity in Patients with Early Type 2 Diabetes Mellitus

STUDY OBJECTIVES: We examined cross-sectional and prospective associations between sleep debt and adiposity measures, as well as homeostatic model assessment-insulin resistance (HOMA-IR) in early type 2 diabetes. METHODS: Prospective data analysis from participants of a randomized controlled trial based on an intensive lifestyle intervention (usual care, diet, or diet and physical activity). Data were collected at baseline, 6 months, and 12 months post-intervention. The study was performed across five secondary care centers in the United Kingdom. Patients (n = 593) with a recent diagnosis of type 2 diabetes were recruited. Objective height and weight were ascertained for obesity status (body mass index [BMI]; ≥ 30 kg/m(2)), waist circumference (cm) for central adiposity, and fasting blood samples drawn to examine insulin resistance (IR). Seven-day sleep diaries were used to calculate weekday sleep debt at baseline, calculated as average weekend sleep duration minus average weekday sleep duration. RESULTS: At baseline, compared to those without weekday sleep debt, those with weekday sleep debt were 72% more likely to be obese (OR = 1.72 [95% CI:1.03–2.88]). At six months, weekday sleep debt was significantly associated with obesity and IR after adjustment, OR = 1.90 (95% CI:1.10–3.30), OR = 2.07 (95% CI:1.02–4.22), respectively. A further increase at 12 months was observed for sleep debt with obesity and IR: OR = 2.10 (95% CI:1.14–3.87), OR = 3.16 (95% CI:1.38–7.24), respectively. For every 30 minutes of weekday sleep debt, the risk of obesity and IR at 12 months increased by 18% and 41%, respectively. CONCLUSIONS: Sleep debt resulted in long-term metabolic disruption, which may promote the progression of type 2 diabetes in newly diagnosed patients. Sleep hygiene/education could be an important factor for future interventions to target early diabetes. CITATION: Arora T, Chen MZ, Cooper AR, Andrews RC, Taheri S. The impact of sleep debt on excess adiposity and insulin sensitivity in patients with early type 2 diabetes mellitus. J Clin Sleep Med 2016;12(5):673–680

A Negative Long Lag from the Optical to the UV Continuum in Fairall 9

We report the detection of a long-timescale negative lag, where the blue bands lag the red bands, in the nearby Seyfert 1 galaxy Fairall 9. Active Galactic Nuclei (AGN) light curves show variability over a wide range of timescales. By measuring time lags between different wavelengths, the otherwise inaccessible structure and kinematics of the accretion disk can be studied. One common approach, reverberation mapping, quantifies the continuum and line lags moving outwards through the disk at the light-travel time, revealing the size and temperature profile of the disk. Inspired by numerical simulations, we expect longer lags to exist in AGN light curves that travel inward on longer timescales, tracing the accretion process itself. By analyzing AGN light curves in both temporal and frequency space, we report the detection of long-timescale lags ($\sim -70$ days) in Fairall 9 which propagate in the opposite direction to the reverberation lag. The short continuum lag ($<10$ days) is also detected and is consistent with reverberation lags reported in the literature. When fitting the longer lag as a function of frequency with a model motivated by the thin disk model, we find that the disk scale height likely increases outward in the disk. This detection raises the exciting prospect of mapping accretion disk structures across a wide range of AGN parameters.Comment: 24 pages, 14 figures, submitted to Ap