The Small-Scale Physical Structure and Fragmentation Difference of Two Embedded Intermediate Mass Protostars in Orion

Intermediate-mass (IM) protostars, the bridge between the very common solar-like protostars and the more massive, but rarer, O and B stars, can only be studied at high physical spatial resolutions in a handful of clouds. In this paper, we present and analyze the continuum results from an observing campaign at the Submillimeter Array (SMA) targeting two well-studied IM protostars in Orion, NGC 2071 and L1641 S3 MMS 1. The extended SMA (eSMA) probes structure at angular resolutions up to 0".2, revealing protostellar disks on scales of ∼200 AU. Continuum flux measurements on these scales indicate that a significant amount of mass, a few tens of M_⊙, is present. Envelope, stellar, and disk masses are derived using compact, extended, and eSMA configurations and compared against spectral energy distribution fitting models. We hypothesize that fragmentation into three components occurred within NGC 2071 at an early time, when the envelopes were less than 10% of their current masses, e.g., <0.5 M. No fragmentation occurred for L1641 S3 MMS 1. For NGC 2071, evidence is given that the bulk of the envelope material currently around each source was accreted after the initial fragmentation. In addition, about 30% of the total core mass is not yet associated to one of the three sources. A global accretion model is favored and a potential accretion history of NGC 2071 is presented. It is shown that the relatively low level of fragmentation in NGC 2071 was stifled compared to the expected fragmentation from a Jeans argument. Similarly, the lack of fragmentation in L1641 S3 MMS 1 is likely due to similar arguments

Inflation and Kahler Stabilization of the Dilaton

The problems of attempting inflationary model-building in a theory containing a dilaton are explained. In particular, I study the shape of the dilaton potential today and during inflation, based on a weakly-coupled heterotic string model where corrections to the Kahler potential are assumed to be responsible for dilaton stabilization. Although no specific model-building is attempted, if the inflationary energy density is related to the scale of gaugino condensation, then the dilaton may be stabilized close enough to today's value that there is no significant change in the GUT scale coupling. This can occur in a very wide range of models, and helps to provide some justification for the standard predictions of the spectral index. I explain how this result can ultimately be traced to the supersymmetry structure of the theory.Comment: 12 pages, submitted to PR

Fingerprinting the Substrate Specificity of M1 and M17 Aminopeptidases of Human Malaria, Plasmodium falciparum

Plasmodium falciparum, the causative agent of human malaria, expresses two aminopeptidases, PfM1AAP and PfM17LAP, critical to generating a free amino acid pool used by the intraerythrocytic stage of the parasite for proteins synthesis, growth and development. These exopeptidases are potential targets for the development of a new class of anti-malaria drugs.To define the substrate specificity of recombinant forms of these two malaria aminopeptidases we used a new library consisting of 61 fluorogenic substrates derived both from natural and unnatural amino acids. We obtained a detailed substrate fingerprint for recombinant forms of the enzymes revealing that PfM1AAP exhibits a very broad substrate tolerance, capable of efficiently hydrolyzing neutral and basic amino acids, while PfM17LAP has narrower substrate specificity and preferentially cleaves bulky, hydrophobic amino acids. The substrate library was also exploited to profile the activity of the native aminopeptidases in soluble cell lysates of P. falciparum malaria.This data showed that PfM1AAP and PfM17LAP are responsible for majority of the aminopeptidase activity in these extracts. These studies provide specific substrate and mechanistic information important for understanding the function of these aminopeptidases and could be exploited in the design of new inhibitors to specifically target these for anti-malaria treatment

The aminopeptidase inhibitor CHR-2863 is an orally bioavailable inhibitor of murine malaria

Malaria remains a significant risk in many areas of the world, with resistance to the current antimalarial pharmacopeia an everincreasing problem. The M1 alanine aminopeptidase (PfM1AAP) and M17 leucine aminopeptidase (PfM17LAP) are believed to play a role in the terminal stages of digestion of host hemoglobin and thereby generate a pool of free amino acids that are essential for parasite growth and development. Here, we show that an orally bioavailable aminopeptidase inhibitor, CHR-2863, is efficacious against murine malaria

The key glycolytic enzyme phosphofructokinase is involved in resistance to antiplasmodial glycosides

ABSTRACT Plasmodium parasites rely heavily on glycolysis for ATP production and for precursors for essential anabolic pathways, such as the methylerythritol phosphate (MEP) pathway. Here, we show that mutations in the Plasmodium falciparum glycolytic enzyme, phosphofructokinase (PfPFK9), are associated with in vitro resistance to a primary sulfonamide glycoside (PS-3). Flux through the upper glycolysis pathway was significantly reduced in PS-3-resistant parasites, which was associated with reduced ATP levels but increased flux into the pentose phosphate pathway. PS-3 may directly or indirectly target enzymes in these pathways, as PS-3-treated parasites had elevated levels of glycolytic and tricarboxylic acid (TCA) cycle intermediates. PS-3 resistance also led to reduced MEP pathway intermediates, and PS-3-resistant parasites were hypersensitive to the MEP pathway inhibitor, fosmidomycin. Overall, this study suggests that PS-3 disrupts core pathways in central carbon metabolism, which is compensated for by mutations in PfPFK9, highlighting a novel metabolic drug resistance mechanism in P. falciparum. IMPORTANCE Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue, causing 405,000 deaths and 228 million cases in 2018. Understanding key metabolic processes in malaria parasites is critical to the development of new drugs to combat this major infectious disease. The Plasmodium glycolytic pathway is essential to the malaria parasite, providing energy for growth and replication and supplying important biomolecules for other essential Plasmodium anabolic pathways. Despite this overreliance on glycolysis, no current drugs target glycolysis, and there is a paucity of information on critical glycolysis targets. Our work addresses this unmet need, providing new mechanistic insights into this key pathway

Comment on ‘‘Post-Wildfire Logging Hinders Regeneration and Increases Fire Risk’’

Donato et al. (Brevia, 20 January 2006, p. 352) concluded that logging after wildfire kills natural regeneration and increases fire risk. We argue that their paper lacks adequate context and supporting information to be clearly interpreted by scientists, resource managers, policy-makers, and the public

Screening the medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18

Malaria is a parasitic disease that remains a global health burden. The ability of the parasite to rapidly develop resistance to therapeutics drives an urgent need for the delivery of new drugs. The Medicines for Malaria Venture have compounds known for their antimalarial ac- tivity, but not necessarily the molecular targets. In this study, we assess the ability of the “MMV 400” compounds to inhibit the activity of three metalloaminopeptidases from Plasmo- dium falciparum, PfA-M1, PfA-M17 and PfM18 AAP. We have developed a multiplex assay system to allow rapid primary screening of compounds against all three metalloaminopepti- dases, followed by detailed analysis of promising compounds. Our results show that there were no PfM18AAP inhibitors, whereas two moderate inhibitors of the neutral aminopepti- dases PfA-M1 and PfA-M17 were identified. Further investigation through structure-activity relationship studies and molecular docking suggest that these compounds are competitive inhibitors with novel binding mechanisms, acting through either non-classical zinc coordina- tion or independently of zinc binding altogether. Although it is unlikely that inhibition of PfA- M1 and/or PfA-M17 is the primary mechanism responsible for the antiplasmodial activity re- ported for these compounds, their detailed characterization, as presented in this work, pave the way for their further optimization as a novel class of dual PfA-M1/PfA-M17 inhibitors uti- lising non-classical zinc binding groups

Overdiagnosis and overtreatment of breast cancer: Progression of ductal carcinoma in situ: the pathological perspective

Ductal carcinoma in situ (DCIS) is encountered much more frequently in the screening population compared to the symptomatic setting. The behaviour of DCIS is highly variable and this presents difficulties in choosing appropriate treatment strategies for individual cases. This review discusses the current data on the frequency and rate of progression of DCIS, the value and limitations of clinicopathological and biological variables in predicting disease behaviour and suggests strategies to develop more robust means of predicting progression of DCIS

Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors

Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics

Autonomous vehicle interactions in the urban street environment: A research agenda

© ICE Publishing 2018. All rights reserved. The Venturer project is trialling an autonomous vehicle (AV) in the context of use on urban roads. This paper summarises a literature review undertaken to assist in developing a research agenda for the trialling. The first contribution of the paper is a framework of four use scenarios for AVs as follows: (1) fully segregated AV network, (2) motorway or expressway network, (3) typical urban network, (4) shared space. The paper then focuses on a review of the social interactions in the street environment and discusses issues concerning human behaviour in relation to autonomy. The second contribution of the paper is a set of research questions for AV trialling in relation to other road users, including, pedestrians and cyclists, which have emerged from the literature review.