Activated AKT/PKB signaling in C. elegans uncouples temporally distinct outputs of DAF-2/insulin-like signaling

BACKGROUND: In the nematode, Caenorhabditis elegans, a conserved insulin-like signaling pathway controls larval development, stress resistance and adult lifespan. AGE-1, a homolog of the p110 catalytic subunit of phosphoinositide 3-kinases (PI3K) comprises the major known effector pathway downstream of the insulin receptor, DAF-2. Phospholipid products of AGE-1/PI3K activate AKT/PKB kinase signaling via PDK-1. AKT/PKB signaling antagonizes nuclear translocation of the DAF-16/FOXO transcription factor. Reduced AGE-1/PI3K signaling permits DAF-16 to direct dauer larval arrest and promote long lifespan in adult animals. In order to study the downstream effectors of AGE-1/PI3K signaling in C. elegans, we conducted a genetic screen for mutations that suppress the constitutive dauer arrest phenotype of age-1(mg109) animals. RESULTS: This report describes mutations recovered in a screen for suppressors of the constitutive dauer arrest (daf-C) phenotype of age-1(mg109). Two mutations corresponded to alleles of daf-16. Two mutations were gain-of-function alleles in the genes, akt-1 and pdk-1, encoding phosphoinositide-dependent serine/threonine kinases. A fifth mutation, mg227, located on chromosome X, did not correspond to any known dauer genes, suggesting that mg227 may represent a new component of the insulin pathway. Genetic epistasis analysis by RNAi showed that reproductive development in age-1(mg109);akt-1(mg247) animals was dependent on the presence of pdk-1. Similarly, reproductive development in age-1(mg109);pdk-1(mg261) animals was dependent on akt-1. However, reproductive development in age-1(mg109); mg227 animals required only akt-1, and pdk-1 activity was dispensable in this background. Interestingly, while mg227 suppressed dauer arrest in age-1(mg109) animals, it enhanced the long lifespan phenotype. In contrast, akt-1(mg247) and pdk-1(mg261) did not affect lifespan or stress resistance, while both daf-16 alleles fully suppressed these phenotypes. CONCLUSION: A screen for suppressors of PI3K mutant phenotypes identified activating mutations in two known pathway components, providing insights into their regulation. In particular, the interdependence of akt-1 and pdk-1, even in activated forms, supports the existence of AGE-1-independent pathways for these phospholipid-dependent kinases. Phenotypic analysis of these alleles shows that the larval and adult outputs of AGE-1/PI3K are fully separable in these mutants

Evidence from K2 for rapid rotation in the descendant of an intermediate-mass star

Using patterns in the oscillation frequencies of a white dwarf observed by K2, we have measured the fastest rotation rate, 1.13(02) hr, of any isolated pulsating white dwarf known to date. Balmer-line fits to follow-up spectroscopy from the SOAR telescope show that the star (SDSSJ0837+1856, EPIC 211914185) is a 13,590(340) K, 0.87(03) solar-mass white dwarf. This is the highest mass measured for any pulsating white dwarf with known rotation, suggesting a possible link between high mass and fast rotation. If it is the product of single-star evolution, its progenitor was a roughly 4.0 solar-mass main-sequence B star; we know very little about the angular momentum evolution of such intermediate-mass stars. We explore the possibility that this rapidly rotating white dwarf is the byproduct of a binary merger, which we conclude is unlikely given the pulsation periods observed.Comment: 5 pages, 4 figure, 1 table; accepted for publication in The Astrophysical Journal Letter

PHarmacist Avoidance or Reductions in Medical Costs in CRITically Ill Adults: PHARM-CRIT Study

OBJECTIVES: To comprehensively classify interventions performed by ICU clinical pharmacists and quantify cost avoidance generated through their accepted interventions. DESIGN: A multicenter, prospective, observational study was performed between August 2018 and January 2019. SETTING: Community hospitals and academic medical centers in the United States. PARTICIPANTS: ICU clinical pharmacists. INTERVENTIONS: Recommendations classified into one of 38 intervention categories (divided into six unique sections) associated with cost avoidance. MEASUREMENTS AND MAIN RESULTS: Two-hundred fifteen ICU pharmacists at 85 centers performed 55,926 interventions during 3,148 shifts that were accepted on 27,681 adult patient days and generated $23,404,089 of cost avoidance. The quantity of accepted interventions and cost avoidance generated in six established sections was adverse drug event prevention (5,777 interventions;$5,822,539 CA), resource utilization (12,630 interventions; $4,491,318), individualization of patient care (29,284 interventions;$9,680,036 cost avoidance), prophylaxis (1,639 interventions; $1,414,465 cost avoidance), hands-on care (1,828 interventions;$1,339,621 cost avoidance), and administrative/supportive tasks (4,768 interventions; $656,110 cost avoidance). Mean cost avoidance was$418 per intervention, $845 per patient day, and$7,435 per ICU pharmacist shift. The annualized cost avoidance from an ICU pharmacist is $1,784,302. The potential monetary cost avoidance to pharmacist salary ratio was between$3.3:1 and $9.6:1. CONCLUSIONS: Pharmacist involvement in the care of critically ill patients results in significant avoidance of healthcare costs, particularly in the areas of individualization of patient care, adverse drug event prevention, and resource utilization. The potential monetary cost avoidance to pharmacist salary ratio employing an ICU clinical pharmacist is between$3.3:1 and $9.6:1

Spin 1 inversion: a Majorana tensor force for deuteron alpha scattering

We demonstrate, for the first time, successful S-matrix to potential inversion for spin one projectiles with non-diagonal $S^j_{ll'}$ yielding a $T_{\rm R}$ interaction. The method is a generalization of the iterative-perturbative, IP, method. We present a test case indicating the degree of uniqueness of the potential. The method is adapted, using established procedures, into direct observable to potential inversion, fitting $\sigma$, ${\rm i}T_{11}$, $T_{20}$, $T_{21}$ and $T_{22}$ for d + alpha scattering over a range of energies near 10 MeV. The $T_{\rm R}$ interaction which we find is very different from that proposed elsewhere, both real and imaginary parts being very different for odd and even parity channels.Comment: 7 pages Revtex, 4 ps figure

Identifying Individuals at Risk for Fracture in Guatemala

INTRODUCTION: The FRAX calculator combines a set of clinical risk factors with country-specific incidence rates to determine the ten-year absolute risk of major osteoporotic fracture. However, regional or country-specific databases from Central American countries are not available. We compared the use of various FRAX databases and the Pluijm algorithm in determining risk of fracture. METHODS: We collected clinical risk factor data needed for the FRAX calculator and Pluijm algorithm of Hispanic women in Guatemala and calculated the FRAX absolute risk measures of major osteoporotic fracture and hip fracture. Subjects were postmenopausal women greater than age 40 with no history of using medication that affect bone. A random sample of 204 women in 34 different regions women in Guatemala City was visited in their homes to complete the surveys. The Pluijm risk score and FRAX risk score using the US Hispanic, Spain, and Mexican databases were calculated. RESULTS: We used the US NOF guidelines for treatment which suggest a treatment threshold for patients with a 10-year hip fracture probability ≥ 3% or a 10-year major osteoporotic fracture risk ≥ 20%. The number of patients meeting the suggested threshold limits for treatment using the Spain and Mexico calculators were identical. There was 100% conformity in threshold limits for both hip and major osteoporotic fracture risk. The mean conformity for any fracture risk between US Hispanic and the other two databases was 97.5%. Conformity was 99.0% based on major osteoporotic fracture and 97.5% based on risk of hip fracture. The Pluijm evaluation shows conformity of 87.2% and 83.3%, respectively, when compared to the US Hispanic and Spain/Mexico FRAX thresholds for risk of fracture. DISCUSSION: Although the different FRAX databases provide variations in the absolute risk of fracture, the overall conformity to treatment thresholds amongst the US Hispanic, Spain, and Mexico databases show the database used would have little effect as to the decision to treat. The Pluijm tool conforms to the FRAX thresholds and can be used as well. It does not matter which country-specific calculator or assessment tool is used, as there are a similar number of patients that would meet the intervention threshold

Asteroseismology of PG 1541++651 and BPM 31594 with TESS

We present the photometric data from TESS for two known ZZ Ceti stars, PG 1541+651 and BPM 31594. Before TESS, both objects only had observations from short runs from ground-based facilities, with three and one period detected, respectively. The TESS data allowed the detection of multiple periodicities, 12 for PG 1541$+$651, and six for BPM 31594, which enables us to perform a detailed asteroseismological study. For both objects we found a representative asteroseismic model with canonical stellar mass ~ 0.61 Msun and thick hydrogen envelopes, thicker than 10^(-5.3) M_*. The detection of triplets in the Fourier transform also allowed us to estimate mean rotation periods, being ~22 h for PG 1541+651 and 11.6 h for BPM 31594, which is consistent with range of values reported for other ZZ Ceti stars.Comment: 12 pages, 11 figures. Accepted for publication in MNRA

The photometric variability of massive stars due to gravity waves excited by core convection

Massive stars die in catastrophic explosions, which seed the interstellar medium with heavy elements and produce neutron stars and black holes. Predictions of the explosion's character and the remnant mass depend on models of the star's evolutionary history. Models of massive star interiors can be empirically constrained by asteroseismic observations of gravity wave oscillations. Recent photometric observations reveal a ubiquitous red noise signal on massive main sequence stars; a hypothesized source of this noise is gravity waves driven by core convection. We present the first 3D simulations of massive star convection extending from the star's center to near its surface, with realistic stellar luminosities. Using these simulations, we make the first prediction of photometric variability due to convectively-driven gravity waves at the surfaces of massive stars, and find that gravity waves produce photometric variability of a lower amplitude and lower characteristic frequency than the observed red noise. We infer that the photometric signal of gravity waves excited by core convection is below the noise limit of current observations, so the red noise must be generated by an alternative process.Comment: As accepted for publication in Nature Astronomy except for final editorial revisions. Supplemental materials available online at https://doi.org/10.5281/zenodo.7764997 . We have also sonified our results to make them more accessible, see https://github.com/evanhanders/gmode_variability_paper/blob/main/sound/gmode_sonification.pd

Synthesis of spiroacetals using functionalised titanium carbenoids

Alkylidenation of lactones with functionalised titanium carbenoid reagents (Schrock carbenes) followed by acid-induced cyclisation of the resulting enol ethers constitutes a new method for the preparation of [4.4], [4.5] and [5.5] spiroacetals (1,6-dioxaspiro[4.4]nonanes, 1,6-dioxaspiro[4.5]decanes and 1,7-dioxaspiro[5.5]undecanes, respectively, sometimes termed 5,5-, 5,6- and 6,6-spiroketals). The titanium carbenoids are easily generated from readily available thioacetals

Pulsating H-deficient WDs and pre-WDs observed with TESS: V. Discovery of two new DBV pulsators, WD J152738.4-450207.4 and WD 1708-871, and asteroseismology of the already known DBV stars PG 1351+489, EC 20058-5234, and EC 04207-4748

The {\sl TESS} space mission has recently demonstrated its great potential to discover new pulsating white dwarf and pre-white dwarf stars, and to detect periodicities with high precision in already known white-dwarf pulsators. We report the discovery of two new pulsating He-rich atmosphere white dwarfs (DBVs) and present a detailed asteroseismological analysis of three already known DBV stars employing observations collected by the {\sl TESS} mission along with ground-based data. We extracted frequencies from the {\sl TESS} light curves of these DBV stars using a standard pre-whitening procedure to derive the potential pulsation frequencies. All the oscillation frequencies that we found are associated with $g$-mode pulsations with periods spanning from $\sim 190$ s to $\sim 936$ s. We find hints of rotation from frequency triplets in some of the targets, including the two new DBVs. For three targets, we find constant period spacings, which allowed us to infer their stellar masses and constrain the harmonic degree $\ell$ of the modes. We also performed period-to-period fit analyses and found an asteroseismological model for three targets, with stellar masses generally compatible with the spectroscopic masses. Obtaining seismological models allowed us to estimate the seismological distances and compare them with the precise astrometric distances measured with {\it Gaia}. We find a good agreement between the seismic and the astrometric distances for three stars (PG~1351+489, EC~20058$-$5234, and EC~04207$-$4748), although for the other two stars (WD~J152738.4$-$50207 and WD~1708$-$871), the discrepancies are substantial. The high-quality data from the {\sl TESS} mission continue to provide important clues to determine the internal structure of pulsating pre-white dwarf and white dwarf stars through the tools of asteroseismology.Comment: 22 pages, 27 figures, 21 tables. To be published in Astronomy & Astrophysic

Metabolic Effects of Acute Thiamine Depletion Are Reversed by Rapamycin in Breast and Leukemia Cells

Thiamine-dependent enzymes (TDEs) control metabolic pathways that are frequently altered in cancer and therefore present cancer-relevant targets. We have previously shown that the recombinant enzyme thiaminase cleaves and depletes intracellular thiamine, has growth inhibitory activity against leukemia and breast cancer cell lines, and that its growth inhibitory effects were reversed in leukemia cell lines by rapamycin. Now, we first show further evidence of thiaminase therapeutic potential by demonstrating its activity against breast and leukemia xenografts, and against a primary leukemia xenograft. We therefore further explored the metabolic effects of thiaminase in combination with rapamycin in leukemia and breast cell lines. Thiaminase decreased oxygen consumption rate and increased extracellular acidification rate, consistent with the inhibitory effect of acute thiamine depletion on the activity of the TDEs pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes; these effects were reversed by rapamycin. Metabolomic studies demonstrated intracellular thiamine depletion and the presence of the thiazole cleavage product in thiaminase-treated cells, providing validation of the experimental procedures. Accumulation of ribose and ribulose in both cell lines support the thiaminase-mediated suppression of the TDE transketolase. Interestingly, thiaminase suppression of another TDE, branched chain amino ketoacid dehydrogenase (BCKDH), showed very different patterns in the two cell lines: in RS4 leukemia cells it led to an increase in BCKDH substrates, and in MCF-7 breast cancer cells it led to a decrease in BCKDH products. Immunoblot analyses showed corresponding differences in expression of BCKDH pathway enzymes, and partial protection of thiaminase growth inhibition by gabapentin indicated that BCKDH inhibition may be a mechanism of thiaminase-mediated toxicity. Surprisingly, most of thiaminase-mediated metabolomic effects were also reversed by rapamycin. Thus, these studies demonstrate that acute intracellular thiamine depletion by recombinant thiaminase results in metabolic changes in thiamine-dependent metabolism, and demonstrate a previously unrecognized role of mTOR signaling in the regulation of thiamine-dependent metabolism