A Characterization of the ALMA Phasing System at 345 GHz

The development of the Atacama Large Millimeter/submillimeter Array (ALMA) phasing system (APS) has allowed ALMA to function as an extraordinarily sensitive station for very long baseline interferometry (VLBI) at frequencies of up to 230 GHz (~1.3 mm). Efforts are now underway to extend use of the APS to 345 GHz (~0.87 mm). Here we report a characterization of APS performance at 345 GHz based on a series of tests carried out between 2015-2021, including a successful global VLBI test campaign conducted in 2018 October in collaboration with the Event Horizon Telescope (EHT).Comment: 22 pages, 11 figures, 7 tables, accepted for publication in PAS

New in vitro interaction-parasite reduction ratio assay for early derisk in clinical development of antimalarial combinations

The development and spread of drug-resistant phenotypes substantially threaten malaria control efforts. Combination therapies have the potential to minimize the risk of resistance development but require intensive preclinical studies to determine optimal combination and dosing regimens. To support the selection of new combinations, we developed a novel in vitro-in silico combination approach to help identify the pharmacodynamic interactions of the two antimalarial drugs in a combination which can be plugged into a pharmacokinetic/pharmacodynamic model built with human monotherapy parasitological data to predict the parasitological endpoints of the combination. This makes it possible to optimally select drug combinations and doses for the clinical development of antimalarials. With this assay, we successfully predicted the endpoints of two phase 2 clinical trials in patients with the artefenomel-piperaquine and artefenomel-ferroquine drug combinations. In addition, the predictive performance of our novel in vitro model was equivalent to that of the humanized mouse model outcome. Last, our more informative in vitro combination assay provided additional insights into the pharmacodynamic drug interactions compared to the in vivo systems, e.g., a concentration-dependent change in the maximum killing effect (Emax) and the concentration producing 50% of the killing maximum effect (EC50) of piperaquine or artefenomel or a directional reduction of the EC50 of ferroquine by artefenomel and a directional reduction of Emax of ferroquine by artefenomel. Overall, this novel in vitro-in silico-based technology will significantly improve and streamline the economic development of new drug combinations for malaria and potentially also in other therapeutic areas

Zooming towards the Event Horizon - mm-VLBI today and tomorrow

Global VLBI imaging at millimeter and sub-millimeter wavelength overcomes the opacity barrier of synchrotron self-absorption in AGN and opens the direct view into sub-pc scale regions not accessible before. Since AGN variability is more pronounced at short millimeter wavelength, mm-VLBI can reveal structural changes in very early stages after outbursts. When combined with observations at longer wavelength, global 3mm and 1mm VLBI adds very detailed information. This helps to determine fundamental physical properties at the jet base, and in the vicinity of super-massive black holes at the center of AGN. Here we present new results from multi-frequency mm-VLBI imaging of OJ287 during a major outburst. We also report on a successful 1.3mm VLBI experiment with the APEX telescope in Chile. This observation sets a new record in angular resolution. It also opens the path towards future mm-VLBI with ALMA, which aims at the mapping of the black hole event horizon in nearby galaxies, and the study of the roots of jets in AGN.Comment: 6 pages, to appear in 11th European VLBI Network Symposium, ed. P. Charlot et al., Bordeaux (France), October 9-12, 201

Properties of Interfaces in the two and three dimensional Ising Model

To investigate order-order interfaces, we perform multimagnetical Monte Carlo simulations of the $2D$ and $3D$ Ising model. Following Binder we extract the interfacial free energy from the infinite volume limit of the magnetic probability density. Stringent tests of the numerical methods are performed by reproducing with high precision exact $2D$ results. In the physically more interesting $3D$ case we estimate the amplitude $F^s_0$ of the critical interfacial tension $F^s = F^s_0 t^\mu$ to be $F^s_0 = 1.52 \pm 0.05$. This result is in good agreement with a previous MC calculation by Mon, as well as with experimental results for related amplitude ratios. In addition, we study in some details the shape of the magnetic probability density for temperatures below the Curie point.Comment: 25 pages; sorry no figures include

Parasite viability as a measure of in vivo drug activity in preclinical and early clinical antimalarial drug assessment

The rate at which parasitemia declines in a host after treatment with an antimalarial drug is a major metric for assessment of antimalarial drug activity in preclinical models and in early clinical trials. However, this metric does not distinguish between viable and nonviable parasites. Thus, enumeration of parasites may result in underestimation of drug activity for some compounds, potentially confounding its use as a metric for assessing antimalarial activity in vivo. Here, we report a study of the effect of artesunate on Plasmodium falciparum viability in humans and in mice. We first measured the drug effect in mice by estimating the decrease in parasite viability after treatment using two independent approaches to estimate viability. We demonstrate that, as previously reported in humans, parasite viability declines much faster after artesunate treatment than does the decline in parasitemia (termed parasite clearance). We also observed that artesunate kills parasites faster at higher concentrations, which is not discernible from the traditional parasite clearance curve and that each subsequent dose of artesunate maintains its killing effect. Furthermore, based on measures of parasite viability, we could accurately predict the in vivo recrudescence of infection. Finally, using pharmacometrics modeling, we show that the apparent differences in the antimalarial activity of artesunate in mice and humans are partly explained by differences in host removal of dead parasites in the two hosts. However, these differences, along with different pharmacokinetic profiles, do not fully account for the differences in activity. (This study has been registered with the Australian New Zealand Clinical Trials Registry under identifier ACTRN12617001394336.)

First 230 GHz VLBI Fringes on 3C 279 using the APEX Telescope

We report about a 230 GHz very long baseline interferometry (VLBI) fringe finder observation of blazar 3C 279 with the APEX telescope in Chile, the phased submillimeter array (SMA), and the SMT of the Arizona Radio Observatory (ARO). We installed VLBI equipment and measured the APEX station position to 1 cm accuracy (1 sigma). We then observed 3C 279 on 2012 May 7 in a 5 hour 230 GHz VLBI track with baseline lengths of 2800 M$\lambda$ to 7200 M$\lambda$ and a finest fringe spacing of 28.6 micro-arcseconds. Fringes were detected on all baselines with SNRs of 12 to 55 in 420 s. The correlated flux density on the longest baseline was ~0.3 Jy/beam, out of a total flux density of 19.8 Jy. Visibility data suggest an emission region <38 uas in size, and at least two components, possibly polarized. We find a lower limit of the brightness temperature of the inner jet region of about 10^10 K. Lastly, we find an upper limit of 20% on the linear polarization fraction at a fringe spacing of ~38 uas. With APEX the angular resolution of 230 GHz VLBI improves to 28.6 uas. This allows one to resolve the last-photon ring around the Galactic Center black hole event horizon, expected to be 40 uas in diameter, and probe radio jet launching at unprecedented resolution, down to a few gravitational radii in galaxies like M 87. To probe the structure in the inner parsecs of 3C 279 in detail, follow-up observations with APEX and five other mm-VLBI stations have been conducted (March 2013) and are being analyzed.Comment: accepted for publication in A&

The effects of a partitioned var gene repertoire of Plasmodium falciparum on antigenic diversity and the acquisition of clinical immunity

<p>Abstract</p> <p>Background</p> <p>The human malaria parasite <it>Plasmodium falciparum </it>exploits antigenic diversity and within-host antigenic variation to evade the host's immune system. Of particular importance are the highly polymorphic <it>var </it>genes that encode the family of cell surface antigens PfEMP1 (<it>Plasmodium falciparum </it>Erythrocyte Membrane Protein 1). It has recently been shown that in spite of their extreme diversity, however, these genes fall into distinct groups according to chromosomal location or sequence similarity, and that recombination may be confined within these groups.</p> <p>Methods</p> <p>This study presents a mathematical analysis of how recombination hierarchies affect diversity, and, by using simple stochastic simulations, investigates how intra- and inter-genic diversity influence the rate at which individuals acquire clinical immunity.</p> <p>Results</p> <p>The analysis demonstrates that the partitioning of the <it>var </it>gene repertoire has a limiting effect on the total diversity attainable through recombination and that the limiting effect is strongly influenced by the respective sizes of each of the partitions. Furthermore, by associating expression of one of the groups with severe malaria it is demonstrated how a small number of infections can be sufficient to protect against disease despite a seemingly limitless number of possible non-identical repertoires.</p> <p>Conclusion</p> <p>Recombination hierarchies within the <it>var </it>gene repertoire of <it>P. falciparum </it>have a severe effect on strain diversity and the process of acquiring immunity against clinical malaria. Future studies will show how the existence of these recombining groups can offer an evolutionary advantage in spite of their restriction on diversity.</p

How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials?

Malaria continues to be an enormous global health challenge, with millions of new infections and deaths reported annually. This is partly due to the development of resistance by the malaria parasite to the majority of established anti-malarial drugs, a situation that continues to hamper attempts at controlling the disease. This has spurred intensive drug discovery endeavours geared towards identifying novel, highly active anti-malarial drugs, and the identification of quality leads from natural sources would greatly augment these efforts. The current reality is that other than compounds that have their foundation in historic natural products, there are no other compounds in drug discovery as part of lead optimization projects and preclinical development or further that have originated from a natural product start-point in recent years. This paper briefly presents both classical as well as some more modern, but underutilized, approaches that have been applied outside the field of malaria, and which could be considered in enhancing the potential of natural products to provide or inspire the development of anti-malarial lead compounds