Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies

Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine. In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin. The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT. Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated haemoglobin degradation. Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes.This work was funded in part by the National Institutes of Health (R01 AI50234, AI124678 and AI109023) and a Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Diseases award to D.A.F. This research also received funding from the Portuguese Fundacao para a Ciencia e Tecnologia (FCT), cofunded by Programa Operacional Regional do Norte (ON.2-O Novo Norte); from the Quadro de Referencia Estrategico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and from the Projeto Estrategico - LA 26 - 2013-2014 (PEst-C/SAU/LA0026/2013). M.I.V. is the recipient of a postdoctoral fellowship from FCT/Ministerio da Ciencia e Ensino Superior, Portugal-MCES (SFRH/BPD/76614/2011). A.M.L. was supported by an Australian National Health and Medical Research Council (NHMRC) Overseas Biomedical Fellowship (585519). R.E.M. was supported by an NHMRC RD Wright Biomedical Fellowship (1053082). A.C.U. was supported by an Irving scholarship from Columbia University. We thank Dr Andrea Ecker for her help with plasmid design and Pedro Ferreira for his expert help with Fig. 6.info:eu-repo/semantics/publishedVersio

Ni-based bimetallic heterogeneous catalysts for energy and environmental applications

Bimetallic catalysts have attracted extensive attention for a wide range of applications in energy production and environmental remediation due to their tunable chemical/physical properties. These properties are mainly governed by a number of parameters such as compositions of the bimetallic systems, their preparation method, and their morphostructure. In this regard, numerous efforts have been made to develop “designer” bimetallic catalysts with specific nanostructures and surface properties as a result of recent advances in the area of materials chemistry. The present review highlights a detailed overview of the development of nickel-based bimetallic catalysts for energy and environmental applications. Starting from a materials science perspective in order to obtain controlled morphologies and surface properties, with a focus on the fundamental understanding of these bimetallic systems to make a correlation with their catalytic behaviors, a detailed account is provided on the utilization of these systems in the catalytic reactions related to energy production and environmental remediation. We include the entire library of nickel-based bimetallic catalysts for both chemical and electrochemical processes such as catalytic reforming, dehydrogenation, hydrogenation, electrocatalysis and many other reactions

EEA1, an early endosome-associated protein: EEA1 is a conserved α-helical peripheral membrane-protein flanked by cysteine fingers and contains a calmodulin-binding IQ motif

Early endosomes are cellular compartments receiving endocytosed material and sorting them for vesicular transport to late endosomes and lysosomes or for recycling to the plasma membrane. We have cloned a human cDNA encoding an evolutionarily conserved 180-kDa protein on early endosomes named EEA1 (Early Endosome Antigen1). EEA1 is associated with early endosomes since it co-localizes by immunofluorescence with the transferrin receptor and with Rab5 but not with Rab7. Immunoelectron microscopy shows that it is associated with tubulovesicular early endosomes containing internalized bovine serum albumin-gold. EEA1 is a hydrophilic peripheral membrane protein present in cytosol and membrane fractions. It partitions in the aqueous phase after Triton X-114 solubilization and is extracted from membranes by 0.3 M NaCl. It is a predominantly cu-helical protein sharing 17-20% sequence identity with the myosins and contains a calmodulin-binding IQ motif. It is flanked by metal-binding, cysteine ''finger'' motifs. The COOH-terminal fingers, Cys-X(2)-Cys-X(12)-Cys-X(2)-Cys and Cys-X(2)-Cys-X(16)-Cys-X(2)-Cys, are present within a region that is strikingly homologous with Saccharomyces cerevisiae FAB1 protein required for endocytosis and with Caenarhabditis elegans ZK632. These fingers also show limited conservation with S. cerevisiae VAC1, Vps11, and Vps18p proteins implicated in vacuolar transport. We propose that EEA1 is required for vesicular transport of proteins through early endosomes and that its finger motifs are required for this activity

Omega-3 PUFA metabolism and brain modifications during aging

In Canada, 5.5 million (16% of Canadians) adults are >65 years old and projections suggest this number will be approximately 20% of Canadians by 2024. A major concern regarding old age is a decline in health, especially if this entails a loss of self-sufficiency and independence caused by a decline in cognition. The brain contains 60% of fat and is one of the most concentrated organs in long chain omega-3 fatty acids such as docosahexaenoic acid (DHA). During aging, there are physiological modifications in the metabolism of lipids that could also have consequences on brain structure and levels of DHA. This review will hence discuss the physiological modifications in the metabolism of lipids during aging with a focus on long chain omega-3 and omega-6 fatty acids and also outline the structural and functional modifications of the brain during aging including brain lipid modifications and its relation to higher levels of DHA and cognition. Therefore, in this review, we outline the importance of collecting more data on the biology of aging since it might highly improve our understanding about what are «normal» modifications occurring during aging and what can become pathological

Model-based Cross-correlation Search for Gravitational Waves from the Low-mass X-Ray Binary Scorpius X-1 in LIGO O3 Data

We present the results of a model-based search for continuous gravitational waves from the low-mass X-ray binary Scorpius X-1 using LIGO detector data from the third observing run of Advanced LIGO and Advanced Virgo. This is a semicoherent search that uses details of the signal model to coherently combine data separated by less than a specified coherence time, which can be adjusted to balance sensitivity with computing cost. The search covered a range of gravitational-wave frequencies from 25 to 1600 Hz, as well as ranges in orbital speed, frequency, and phase determined from observational constraints. No significant detection candidates were found, and upper limits were set as a function of frequency. The most stringent limits, between 100 and 200 Hz, correspond to an amplitude h0 of about 10−25 when marginalized isotropically over the unknown inclination angle of the neutron star's rotation axis, or less than 4 × 10−26 assuming the optimal orientation. The sensitivity of this search is now probing amplitudes predicted by models of torque balance equilibrium. For the usual conservative model assuming accretion at the surface of the neutron star, our isotropically marginalized upper limits are close to the predicted amplitude from about 70 to 100 Hz; the limits assuming that the neutron star spin is aligned with the most likely orbital angular momentum are below the conservative torque balance predictions from 40 to 200 Hz. Assuming a broader range of accretion models, our direct limits on gravitational-wave amplitude delve into the relevant parameter space over a wide range of frequencies, to 500 Hz or more

Model-based cross-correlation search for gravitational waves from the low-mass X-ray binary Scorpius X-1 in LIGO O3 data

We present the results of a model-based search for continuous gravitational waves from the low-mass X-ray binary Scorpius X-1 using LIGO detector data from the third observing run of Advanced LIGO, Advanced Virgo and KAGRA. This is a semicoherent search which uses details of the signal model to coherently combine data separated by less than a specified coherence time, which can be adjusted to balance sensitivity with computing cost. The search covered a range of gravitational-wave frequencies from 25Hz to 1600Hz, as well as ranges in orbital speed, frequency and phase determined from observational constraints. No significant detection candidates were found, and upper limits were set as a function of frequency. The most stringent limits, between 100Hz and 200Hz, correspond to an amplitude h0 of about 1e-25 when marginalized isotropically over the unknown inclination angle of the neutron star's rotation axis, or less than 4e-26 assuming the optimal orientation. The sensitivity of this search is now probing amplitudes predicted by models of torque balance equilibrium. For the usual conservative model assuming accretion at the surface of the neutron star, our isotropically-marginalized upper limits are close to the predicted amplitude from about 70Hz to 100Hz; the limits assuming the neutron star spin is aligned with the most likely orbital angular momentum are below the conservative torque balance predictions from 40Hz to 200Hz. Assuming a broader range of accretion models, our direct limits on gravitational-wave amplitude delve into the relevant parameter space over a wide range of frequencies, to 500Hz or more

Search for subsolar-mass black hole binaries in the second part of Advanced LIGO’s and Advanced Virgo’s third observing run

We describe a search for gravitational waves from compact binaries with at least one component with mass 0.2–1.0 M and mass ratio q ≥ 0.1 in Advanced Laser Interferometer Gravitational-Wave Observatory (LIGO) and Advanced Virgo data collected between 2019 November 1, 15:00 UTC and 2020 March 27, 17:00 UTC. No signals were detected. The most significant candidate has a false alarm rate of 0.2 yr−1. We estimate the sensitivity of our search over the entirety of Advanced LIGO’s and Advanced Virgo’s third observing run, and present the most stringent limits to date on the merger rate of binary black holes with at least one subsolar-mass component. We use the upper limits to constrain two fiducial scenarios that could produce subsolar-mass black holes: primordial black holes (PBH) and a model of dissipative dark matter. The PBH model uses recent prescriptions for the merger rate of PBH binaries that include a rate suppression factor to effectively account for PBH early binary disruptions. If the PBHs are monochromatically distributed, we can exclude a dark matter fraction in PBHs fPBH 0.6 (at 90 per cent confidence) in the probed subsolar-mass range. However, if we allow for broad PBH mass distributions, we are unable to rule out fPBH = 1. For the dissipative model, where the dark matter has chemistry that allows a small fraction to cool and collapse into black holes, we find an upper bound fDBH < 10−5 on the fraction of atomic dark matter collapsed into black holes

Advancing South American Water and Climate Science through Multidecadal Convection-Permitting Modeling

South America’s hydroclimate sustains vibrant communities and natural ecosystems of extraordinary biodiversity including the Andes Cordillera, and the Orinoco, La Plata, and Amazon basins. Global warming and land-use change are endangering ecosystem health, exacerbating hydrometeorological extremes, and threatening water and food security for millions of people on the continent (Castellanos et al. 2022). Reductions in rainfall and streamflow have been observed in southern Amazonia, the Cerrado region, northeast Brazil, and Chile (Muñoz et al. 2020; Garreaud et al. 2020; Espinoza et al. 2019; Fu et al. 2013). The increased aridity has affected agricultural yield, water supply for reservoirs, hydropower generation and impacted tens of millions of people in the large metropolitan areas of Sao Paulo, Rio de Janeiro, and Santiago de Chile (Nobre et al. 2016). Andean glaciers, an important source of water, have lost 30% of their area in the tropics and up to 60% in the southern Andes—the highest glacier mass loss rates in the world (Braun et al. 2019; Dussaillant et al. 2019; Reinthaler et al. 2019; Masiokas et al. 2020; Fox-Kemper et al. 2021). Conversely, southeastern South America is facing increasing annual rainfall and intensification of heavy precipitation since the early twentieth century (Doyle et al. 2012; Barros et al. 2015; Pabón-Caicedo et al. 2020; Arias et al. 2021; Gutiérrez et al. 2021; Morales-Yokobori 2021; Seneviratne et al. 2021). Extreme precipitation is projected to intensify throughout the continent (Arias et al. 2021; Seneviratne et al. 2021). This poses significant risk to people and infrastructure along the Andes and other mountainous areas, particularly for lower-income communities living in informal housing (Poveda et al. 2020; Ozturk et al. 2022). The overarching goals of the SAAG community are twofold: improved physical understanding and application-relevant research. Two multidecadal convection-permitting simulations are at the heart of SAAG. The historical simulation will allow us to validate the model and better understand detailed hydroclimate features over the continent, while the future climate simulation will show the projected changes of these features in a warmer climate. Furthermore, SAAG scientists are working directly with local communities, so the information can be used for improved decision making. The specific goals and science questions are as follows; goal 1 Physical understanding: Advance insights and improve prediction of key hydroclimate processes in the region including projected changes in a changing climate and Goal 2, Provide information that can be used by local communities and stakeholders for better informed decision-making in a changing climate