Tackling resistance: Emerging antimalarials and new parasite targets in the era of elimination [version 1; referees: 2 approved]

Malaria remains a significant contributor to global human mortality, and roughly half the world’s population is at risk for infection with Plasmodium spp. parasites. Aggressive control measures have reduced the global prevalence of malaria significantly over the past decade. However, resistance to available antimalarials continues to spread, including resistance to the widely used artemisinin-based combination therapies. Novel antimalarial compounds and therapeutic targets are greatly needed. This review will briefly discuss several promising current antimalarial development projects, including artefenomel, ferroquine, cipargamin, SJ733, KAF156, MMV048, and tafenoquine. In addition, we describe recent large-scale genetic and resistance screens that have been instrumental in target discovery. Finally, we highlight new antimalarial targets, which include essential transporters and proteases. These emerging antimalarial compounds and therapeutic targets have the potential to overcome multi-drug resistance in ongoing efforts toward malaria elimination

Resonant Few-Photon Excitation of a Single-Ion Oscillator

We study the motion of an undamped single-ion harmonic oscillator, resonantly driven with a pulsed radiation pressure force. We demonstrate that a barium ion, initially cooled to the Doppler limit, quickly phase locks to the drive and builds up coherent oscillations above the thermal distribution after scattering of order one hundred photons. In our experiment, this seeded motion is subsequently amplified and then analyzed by Doppler velocimetry. Since the coherent oscillation is conditional upon the internal quantum state of the ion, this motional excitation technique could be useful in atomic or molecular single-ion spectroscopy experiments, providing a simple protocol for state readout of non-fluorescing ions with partially closed-cycle transitions

Polymer matrix and graphite fiber interface study

Hercules AS4 graphite fiber, unsized, or with EPON 828, PVA, or polysulfone sizing, was combined with three different polymer matrices. These included Hercules 3501-6 epoxy, Hercules 4001 bismaleimide, and Hexcel F155 rubber toughened epoxy. Unidirectional composites in all twelve combinations were fabricated and tested in transverse tension and axial compression. Quasi-isotropic laminates were tested in axial tension and compression, flexure, interlaminar shear, and tensile impact. All tests were conducted at both room temperature, dry and elevated temperature, and wet conditions. Single fiber pullout testing was also performed. Extensive scanning electron microphotographs of fracture surfaces are included, along with photographs of single fiber pullout failures. Analytical/experimental correlations are presented, based on the results of a finite element micromechanics analysis. Correlations between matrix type, fiber sizing, hygrothermal environment, and loading mode are presented. Results indicate that the various composite properties were only moderately influenced by the fiber sizings utilized

Optical Pumping of TeH+: Implications for the Search for Varying mp/me

Molecular overtone transitions provide optical frequency transitions sensitive to variation in the proton-to-electron mass ratio ($\mu\equiv m_p/m_e$). However, robust molecular state preparation presents a challenge critical for achieving high precision. Here, we characterize infrared and optical-frequency broadband laser cooling schemes for TeH$^+$, a species with multiple electronic transitions amenable to sustained laser control. Using rate equations to simulate laser cooling population dynamics, we estimate the fractional sensitivity to $\mu$ attainable using TeH$^+$. We find that laser cooling of TeH$^+$ can lead to significant improvements on current $\mu$ variation limits

Ultralow-threshold, continuous-wave upconverting lasing from subwavelength plasmons.

Miniaturized lasers are an emerging platform for generating coherent light for quantum photonics, in vivo cellular imaging, solid-state lighting and fast three-dimensional sensing in smartphones1-3. Continuous-wave lasing at room temperature is critical for integration with opto-electronic devices and optimal modulation of optical interactions4,5. Plasmonic nanocavities integrated with gain can generate coherent light at subwavelength scales6-9, beyond the diffraction limit that constrains mode volumes in dielectric cavities such as semiconducting nanowires10,11. However, insufficient gain with respect to losses and thermal instabilities in nanocavities has limited all nanoscale lasers to pulsed pump sources and/or low-temperature operation6-9,12-15. Here, we show continuous-wave upconverting lasing at room temperature with record-low thresholds and high photostability from subwavelength plasmons. We achieve selective, single-mode lasing from Yb3+/Er3+-co-doped upconverting nanoparticles conformally coated on Ag nanopillar arrays that support a single, sharp lattice plasmon cavity mode and greater than wavelength λ/20 field confinement in the vertical dimension. The intense electromagnetic near-fields localized in the vicinity of the nanopillars result in a threshold of 70 W cm-2, orders of magnitude lower than other small lasers. Our plasmon-nanoarray upconverting lasers provide directional, ultra-stable output at visible frequencies under near-infrared pumping, even after six hours of constant operation, which offers prospects in previously unrealizable applications of coherent nanoscale light

Multiple Functionality in Nanotube Transistors

Calculations of quantum transport in a carbon nanotube transistor show that such a device offers unique functionality. It can operate as a ballistic field-effect transistor, with excellent characteristics even when scaled to 10 nm dimensions. At larger gate voltages, channel inversion leads to resonant tunneling through an electrostatically defined nanoscale quantum dot. Thus the transistor becomes a gated resonant tunelling device, with negative differential resistance at a tunable threshold. For the dimensions considered here, the device operates in the Coulomb blockade regime, even at room temperature.Comment: To appear in Phys. Rev. Let

Subband population in a single-wall carbon nanotube diode

We observe current rectification in a molecular diode consisting of a semiconducting single-wall carbon nanotube and an impurity. One half of the nanotube has no impurity, and it has a current-voltage (I-V) charcteristic of a typical semiconducting nanotube. The other half of the nanotube has the impurity on it, and its I-V characteristic is that of a diode. Current in the nanotube diode is carried by holes transported through the molecule's one-dimensional subbands. At 77 Kelvin we observe a step-wise increase in the current through the diode as a function of gate voltage, showing that we can control the number of occupied one-dimensional subbands through electrostatic doping.Comment: to appear in Physical Review Letters. 4 pages & 3 figure

Electronic states of metallic and semiconducting carbon nanotubes with bond and site disorder

Disorder effects on the density of states in carbon nanotubes are analyzed by a tight binding model with Gaussian bond or site disorder. Metallic armchair and semiconducting zigzag nanotubes are investigated. In the strong disorder limit, the conduction and valence band states merge, and a finite density of states appears at the Fermi energy in both of metallic and semiconducting carbon nanotubes. The bond disorder gives rise to a huge density of states at the Fermi energy differently from that of the site disorder case. Consequences for experiments are discussed.Comment: Phys. Rev. B: Brief Reports (to be published). Related preprints can be found at http://www.etl.go.jp/~harigaya/NEW.htm

One-electron states and interband optical absorption in single-wall carbon nanotubes

Explicit expressions for the wave functions and dispersion equation for the band p - electrons in single-wall carbon nanotubes are obtained within the method of zero-range potentials. They are then used to investigate the absorption spectrum of polarized light caused by direct interband transitions in isolated nanotubes. It is shown that, at least, under the above approximations, the circular dichroism is absent in chiral nanotubes for the light wave propagating along the tube axis. The results obtained are compared with those calculated in a similar way for a graphite plane.Comment: 16 pages, 8 figures, 1 tabl

Decoupling of evolutionary changes in transcription factor binding and gene expression in mammals

To understand the evolutionary dynamics between transcription factor (TF) binding and gene expression in mammals, we compared transcriptional output and the binding intensities for three tissue-specific TFs in livers from four closely related mouse species. For each transcription factor, TF-dependent genes and the TF binding sites most likely to influence mRNA expression were identified by comparing mRNA expression levels between wild-type and TF knockout mice. Independent evolution was observed genome-wide between the rate of change in TF binding and the rate of change in mRNA expression across taxa, with the exception of a small number of TF-dependent genes. We also found that binding intensities are preferentially conserved near genes whose expression is dependent on the TF, and the conservation is shared among binding peaks in close proximity to each other near the TSS. Expression of TF-dependent genes typically showed an increased sensitivity to changes in binding levels as measured by mRNA abundance. Taken together, these results highlight a significant tolerance to evolutionary changes in TF binding intensity in mammalian transcriptional networks and suggest that some TF-dependent genes may be largely regulated by a single TF across evolution