The Hansenula polymorpha PER8 Gene Encodes a Novel Peroxisomal Integral Membrane Protein Involved in Proliferation

We previously described the isolation of mutants of the methylotrophic yeast Hansenula polymorpha that are defective in peroxisome biogenesis. Here, we describe the characterization of one of these mutants, per8, and the cloning of the PER8 gene. In either methanol or methylamine medium, conditions that normally induce the organdies, per8 cells contain no peroxisome-like structures and peroxisomal enzymes are located in the cytosol. The sequence of PER8 predicts that its product (Per8p) is a novel polypeptide of 34 kD, and antibodies against Per8p recognize a protein of 31 kD. Analysis of the primary sequence of Per8p revealed a 39-amino-acid cysteine-rich segment with similarity to the C3HC4 family of zinc-finger motifs. Overexpression of PER8 results in a markedly enhanced increase in peroxisome numbers. We show that Per8p is an integral membrane protein of the peroxisome and that it is concentrated in the membranes of newly formed organdies. We propose that Per8p is a component of the molecular machinery that controls the proliferation of this organelle.

Pharmacogenetics of analgesic drugs

• Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined. • Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications. • While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype–phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the µ-opioid receptor). • Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future. • This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors’ views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain

Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans' Lifespan.

Increased resistance to environmental stress at the cellular level is correlated with the longevity of long-lived mutants and wild-animal species. Moreover, in experimental organisms, screens for increased stress resistance have yielded mutants that are long-lived. To find entry points for small molecules that might extend healthy longevity in humans, we screened ∼100,000 small molecules in a human primary-fibroblast cell line and identified a set that increased oxidative-stress resistance. Some of the hits fell into structurally related chemical groups, suggesting that they may act on common targets. Two small molecules increased C. elegans' stress resistance, and at least 9 extended their lifespan by ∼10-50%. We further evaluated a chalcone that produced relatively large effects on lifespan and were able to implicate the activity of two, stress-response regulators, NRF2/skn-1 and SESN/sesn-1, in its mechanism of action. Our findings suggest that screening for increased stress resistance in human cells can enrich for compounds with promising pro-longevity effects. Further characterization of these compounds may reveal new ways to extend healthy human lifespan

A Pichia pastoris VPS15 homologue is required in selective peroxisome autophagy

Methylotrophic yeasts contain large peroxisomes during growth on methanol. Upon exposure to excess glucose or ethanol these organelles are selectively degraded by autophagy, Here we describe the cloning of a Pichia pastoris gene (PpVPS15) involved ill peroxisome degradation, which is homologous to Saccharomyces cerevisiae VPS15. In methanol-grown cells of a P. pastoris VPS15 deletion strain, the levels of peroxisomal marker enzymes remained high after addition of excess glucose or ethanol. Electron microscopic studies revealed that the organelles were not taken up by vacuoles, suggesting that PpVPS15 is required at an early stage in peroxisome degradation

Magnetic Field scaling of Relaxation curves in Small Particle Systems

We study the effects of the magnetic field on the relaxation of the magnetization of small monodomain non-interacting particles with random orientations and distribution of anisotropy constants. Starting from a master equation, we build up an expression for the time dependence of the magnetization which takes into account thermal activation only over barriers separating energy minima, which, in our model, can be computed exactly from analytical expressions. Numerical calculations of the relaxation curves for different distribution widths, and under different magnetic fields H and temperatures T, have been performed. We show how a \svar scaling of the curves, at different T and for a given H, can be carried out after proper normalization of the data to the equilibrium magnetization. The resulting master curves are shown to be closely related to what we call effective energy barrier distributions, which, in our model, can be computed exactly from analytical expressions. The concept of effective distribution serves us as a basis for finding a scaling variable to scale relaxation curves at different H and a given T, thus showing that the field dependence of energy barriers can be also extracted from relaxation measurements.Comment: 12 pages, 9 figures, submitted to Phys. Rev.

Multi-messenger astronomy of gravitational-wave sources with flexible wide-area radio transient surveys

We explore opportunities for multi-messenger astronomy using gravitational waves (GWs) and prompt, transient low-frequency radio emission to study highly energetic astrophysical events. We review the literature on possible sources of correlated emission of gravitational waves and radio transients, highlighting proposed mechanisms that lead to a short-duration, high-flux radio pulse originating from the merger of two neutron stars or from a superconducting cosmic string cusp. We discuss the detection prospects for each of these mechanisms by low-frequency dipole array instruments such as LWA1, LOFAR and MWA. We find that a broad range of models may be tested by searching for radio pulses that, when de-dispersed, are temporally and spatially coincident with a LIGO/Virgo GW trigger within a \usim 30 second time window and \usim 200 \mendash 500 \punits{deg}^{2} sky region. We consider various possible observing strategies and discuss their advantages and disadvantages. Uniquely, for low-frequency radio arrays, dispersion can delay the radio pulse until after low-latency GW data analysis has identified and reported an event candidate, enabling a \emph{prompt} radio signal to be captured by a deliberately targeted beam. If neutron star mergers do have detectable prompt radio emissions, a coincident search with the GW detector network and low-frequency radio arrays could increase the LIGO/Virgo effective search volume by up to a factor of \usim 2. For some models, we also map the parameter space that may be constrained by non-detections.Comment: 31 pages, 4 figure

Observations of Giant Pulses from Pulsar PSR B0950+08 using LWA1

We report the detection of giant pulse emission from PSR B0950+08 in 24 hours of observations made at 39.4 MHz, with a bandwidth of 16 MHz, using the first station of the Long Wavelength Array, LWA1. We detected 119 giant pulses from PSR B0950+08 (at its dispersion measure), which we define as having SNRs at least 10 times larger than for the mean pulse in our data set. These 119 pulses are 0.035% of the total number of pulse periods in the 24 hours of observations. The rate of giant pulses is about 5.0 per hour. The cumulative distribution of pulse strength $S$ is a steep power law, $N(>S)\propto S^{-4.7}$, but much less steep than would be expected if we were observing the tail of a Gaussian distribution of normal pulses. We detected no other transient pulses in a dispersion measure range from 1 to 90 pc cm$^{-3}$, in the beam tracking PSR B0950+08. The giant pulses have a narrower temporal width than the mean pulse (17.8 ms, on average, vs. 30.5 ms). The pulse widths are consistent with a previously observed weak dependence on observing frequency, which may be indicative of a deviation from a Kolmogorov spectrum of electron density irregularities along the line of sight. The rate and strength of these giant pulses is less than has been observed at $\sim$100 MHz. Additionally, the mean (normal) pulse flux density we observed is less than at $\sim$100 MHz. These results suggest this pulsar is weaker and produces less frequent giant pulses at 39 MHz than at 100 MHz.Comment: 27 pages, 12 figures, typos correcte

A Hexose Transporter Homologue Controls Glucose Repression in the Methylotrophic Yeast Hansenula polymorpha

Peroxisome biogenesis and synthesis of peroxisomal enzymes in the methylotrophic yeast Hansenula polymorpha are under the strict control of glucose repression. We identified an H. polymorpha glucose catabolite repression gene (HpGCR1) that encodes a hexose transporter homologue. Deficiency in GCR1 leads to a pleiotropic phenotype that includes the constitutive presence of peroxisomes and peroxisomal enzymes in glucose-grown cells. Glucose transport and repression defects in a UV-induced gcr1-2 mutant were found to result from a missense point mutation that substitutes a serine residue (Ser85) with a phenylalanine in the second predicted transmembrane segment of the Gcr1 protein. In addition to glucose, mannose and trehalose fail to repress the peroxisomal enzyme, alcohol oxidase in gcr1-2 cells. A mutant deleted for the GCR1 gene was additionally deficient in fructose repression. Ethanol, sucrose, and maltose continue to repress peroxisomes and peroxisomal enzymes normally and therefore, appear to have GCR1-independent repression mechanisms in H. polymorpha. Among proteins of the hexose transporter family of baker’s yeast, Saccharomyces cerevisiae, the amino acid sequence of the H. polymorpha Gcr1 protein shares the highest similarity with a core region of Snf3p, a putative high affinity glucose sensor. Certain features of the phenotype exhibited by gcr1 mutants suggest a regulatory role for Gcr1p in a repression pathway, along with involvement in hexose transport

Analysis of alternative hedging strategies for backgrounding feeder calves in Tennessee

This research evaluated various futures market hedging strategies for feeder cattle backgrounding operations to determine their impact on level and variability of net returns. Improving overall net returns and avoiding risk associated with adverse cash price movements were assumed objectives for the cattle producer backgrounding feeder steers. The hedging strategies were simulated with the use of models represent-ing the typical Tennessee producer\u27s summer and winter feeder cattle backgrounding operations during the 1972-79 period. The strategies simulated included variations of basic, moving average, and point-and-figure analysis hedging strategies and the typical cash sale. The mean and variance of net returns were used as criteria for comparing the effectiveness of the strategies simulated. The primary results of the simulations showed that selective hedging could give larger mean net return and lower variance of net return than the cash market. The basic hedging strategies appeared to perform well when the producer began backgrounding steers in the spring and marketed them in the fall. In almost every observation, the moving average and point-and-figure hedging strategies were superior to the cash market by yielding higher mean net returns with lower variances. Assuming similar production and market conditions to those of the simulation period, the results of this study indicate that a producer can effectively increase his mean net returns with smaller risk compared to the cash market when utilizing the superior selective hedging strategies discussed in this study