Spontaneous onset of homochirality in oligopeptide chains generated in the polymerization of N-carboxyanhydride amino acids in water

ISSN:0169-6149ISSN:1573-087

The pricing of volatility risk in the US equity market

We analyze whether the pricing of volatility risk depends on the asset pricing framework applied in the tests, the specified volatility proxies, and the portfolio sorts used for spanning the asset universe. For this purpose, we compare the results using a macroeconomic and fundamental based asset pricing model using three proxies of volatility and uncertainty, using size/value sorted and industry sector portfolios. Our results reveal that the marginal pricing effect of the VIX volatility factor is strong and statistically significant throughout the models and specifications, while the effect of an EGARCH-based volatility factor is mixed, mostly smaller but with the correct sign. In most cases, the EGARCH factor does not impair the pricing effect of the VIX. The portfolio sorts have a substantial impact on the volatility premiums in both model frameworks. The size of the volatility risk premium is more uniform across the models if the industry sector portfolio sort is used. Finally, the size/value portfolio sort generates larger volatility risk premiums for both models

Symmetry-breaking in chiral polymerisation

We propose a model for chiral polymerisation and investigate its symmetric and asymmetric solutions. The model has a source species which decays into left- and right-handed types of monomer, each of which can polymerise to form homochiral chains; these chains are susceptible to `poisoning' by the opposite handed monomer. Homochiral polymers are assumed to influence the proportion of each type of monomer formed from the precursor. We show that for certain parameter values a positive feedback mechanism makes the symmetric steady-state solution unstable. The kinetics of polymer formation are then analysed in the case where the system starts from zero concentrations of monomer and chains. We show that following a long induction time, extremely large concentrations of polymers are formed for a short time, during this time an asymmetry introduced into the system by a random external perturbation may be massively amplified. The system then approaches one of the steady-state solutions described above.Comment: 26pages, 6 Figure

The catalytic subunit of Plasmodium falciparum casein kinase 2 is essential for gametocytogenesis

Casein kinase 2 (CK2) is a pleiotropic kinase phosphorylating substrates in different cellular compartments in eukaryotes. In the malaria parasite Plasmodium falciparum, PfCK2 is vital for asexual proliferation of blood-stage parasites. Here, we applied CRISPR/Cas9-based gene editing to investigate the function of the PfCK2alpha catalytic subunit in gametocytes, the sexual forms of the parasite that are essential for malaria transmission. We show that PfCK2alpha localizes to the nucleus and cytoplasm in asexual and sexual parasites alike. Conditional knockdown of PfCK2alpha expression prevented the transition of stage IV into transmission-competent stage V gametocytes, whereas the conditional knockout of pfck2a completely blocked gametocyte maturation already at an earlier stage of sexual differentiation. In summary, our results demonstrate that PfCK2alpha is not only essential for asexual but also sexual development of P. falciparum blood-stage parasites and encourage studies exploring PfCK2alpha as a potential target for dual-active antimalarial drugs

Inhibition of lipid oxidation increases glucose metabolism and enhances 2-deoxy-2-[¹⁸F]fluoro-D-glucose uptake in prostate cancer mouse xenografts

Includes bibliographic references.PURPOSE: Prostate cancer (PCa) is the second most common cause of cancer-related death among men in the United States. Due to the lipid-driven metabolic phenotype of Pca, imaging with 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) is suboptimal, since tumors tend to have low avidity for glucose. PROCEDURES: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines. Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro. Systemic etomoxir treatment was used to enhance [¹⁸F]FDG-positron emission tomography ([¹⁸F]FDG-PET) imaging in PCa xenograft mouse models in 24 h. RESULTS: PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [¹⁸F]FDG signal in PCa mouse models. CONCLUSIONS: Inhibition of lipid oxidation plays a major role in elevating glucose metabolism of PCa cells, with potential for imaging enhancement that could also be extended to other cancers

High Current, High frequency ECRIS development program for LHC heavy ion beam application

A research program with the aim of producing pulsed currents with hitherto unequalled intensity of Pb27+, with length and repetition ratecompatible with those desired by CERN (1 mAe / 400 ms / 10 Hz in the context of future heavy ion collisions at LHC) is organised in acollaboration between CERN/GSI/CEA-Grenoble and IN2P3-ISNG.Two main experimental programs will be carried out : (i) tests with the LNS-Catania team on the SERSE superconducting source with a 28 GHzgyrotron, (ii) tests on a non-superconducting source (new source at Grenoble) with a 28 GHz gyrotron. For this purpose CEA/DRFMC hasborrowed from CEA a 28 GHz - 10 kW gyrotron transmitter.The project includes also the construction of a source body, by ISNG, with conventional coils and permanent magnets for working at the frequencyof about 28 GHz and biased up to 60 kV. This source called PHOENIX will run on a test bench at ISN. PHOENIX is an improvement of thepresent ECR4-14.5 GHz/CERN source, having a mirror ratio R=2 at 14.5 GHz, and R=1.7 at 28 GHz (possibly reaching 2.1 T on the axis of thesource), and with a plasma volume up to 2.5 larger.Experiments at 28 GHz will be performed on the SERSE source in Catania at INFN/LNS where both the axial and the hexapolar fields will bevaried so that the mirror ratio is continuously varied up to R=1.6 ; the SERSE source will be also operated at lower magnetic fields such as thosewhich can be produced by conventional magnets (less than 2 T axial field at injection - far from the 28 GHz High-B mode)

Loneliness and the Emotional Experience of Absence

In this paper, we develop an analysis of the structure and content of loneliness. We argue that this is an emotion of absence-an affective state in which certain social goods are regarded as out of reach for the subject of experience. By surveying the range of social goods that appear to be missing from the lonely person's perspective, we see what it is that can make this emotional condition so subjectively awful for those who undergo it, including the profound sense of being unable to realise oneself, in collaboration with others

Local Knockdown of ERK2 in the Adult Mouse Brain Via Adeno-Associated Virus-Mediated RNA Interference

In recent years RNA interference (RNAi) has become a useful genetic tool to downregulate candidate disease genes for which pharmaceutical inhibitors are not available. In combination with viral vectors to trigger RNAi in the mammalian body, it allows the localized and specific manipulation of the expression of single or multiple genes in vivo. The MAP kinases ERK1 and ERK2 are involved in the transduction of extracellular signals to nuclear effectors. A role for ERKs has been proposed in the adult brain in mediating neuronal functions, as for fear learning in the lateral amygdala. To study the role of ERK in anxiety disorders characterized by disturbed fear learning processes we developed Erk-specific RNAi tools and tested the efficacy of a viral Erk2 vector in the adult mouse brain. We found shRNAs that showed silencing of either both ERK1/2 or only ERK2. In particular, our analysis showed that an Erk2-specific shRNA reduced the activity of this gene at comparable efficiency both in vitro and in vivo. This reagent provides a useful tool to study the role of ERK2, for which small molecule inhibitors are not available, in the development of anxiety and other psychiatric disorders

Aberrant phase separation and nucleolar dysfunction in rare genetic diseases

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1-3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6-8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.© 2023. The Author(s)