MmpL3 is the flippase for mycolic acids in mycobacteria

The defining feature of the mycobacterial outer membrane (OM) is the presence of mycolic acids (MAs), which, in part, render the bilayer extremely hydrophobic and impermeable to external insults, including many antibiotics. Although the biosynthetic pathway of MAs is well studied, the mechanism(s) by which these lipids are transported across the cell envelope is(are) much less known. Mycobacterial membrane protein Large 3 (MmpL3), an essential inner membrane (IM) protein, is implicated in MA transport, but its exact function has not been elucidated. It is believed to be the cellular target of several antimycobacterial compounds; however, evidence for direct inhibition of MmpL3 activity is also lacking. Here, we establish that MmpL3 is the MA flippase at the IM of mycobacteria and is the molecular target of BM212, a 1,5-diarylpyrrole compound. We develop assays that selectively access mycolates on the surface of Mycobacterium smegmatis spheroplasts, allowing us to monitor flipping of MAs across the IM. Using these assays, we establish the mechanism of action of BM212 as a potent MmpL3 inhibitor, and use it as a molecular probe to demonstrate the requirement for functional MmpL3 in the transport of MAs across the IM. Finally,we showthat BM212 bindsMmpL3 directly and inhibits its activity. Our work provides fundamental insights into OM biogenesis and MA transport in mycobacteria. Furthermore, our assays serve as an important platform for accelerating the validation of small molecules that target MmpL3, and their development as future antituberculosis drugs

Changes in Tropical Clouds and Atmospheric Circulation Associated with Rapid Adjustment Induced by Increased Atmospheric CO2 A Multiscale Modeling Framework Study

The radiative heating increase due to increased CO2 concentration is the primary source for the rapid adjustment of atmospheric circulation and clouds. In this study, we investigate the rapid adjustment resulting from doubling of CO2 and its physical mechanism using a multiscale modeling framework (MMF). The MMF includes an advanced higher-order turbulence closure in its cloud-resolving model component and simulates realistic shallow and deep cloud climatology and boundary layer turbulence. The rapid adjustment over the tropics is characterized by 1) reduced ascent and descent strengths over the ocean, 2) increased lower tropospheric stability (LTS) over the subsidence region, 3) shoaling of planetary boundary layers over the ocean, 4) increased deep convection over lands and shift of cloud coverage from the ocean to lands, and 5) reduced sensible (SH) and latent heat (LH) fluxes over the oceanic deep convective regions. Unlike conventional general circulation models and another MMF, a reduction in the global-mean shortwave cloud radiative cooling is not simulated, due to the increase in low clouds at lower altitudes over the ocean, resulting from reduced cloud-top entrainment due to strengthened inversion. Changes in regional circulation play a key role in cloud changes and shift of cloud coverage to lands. Weaker energy transport resulting from water vapor and cloud CO2 masking effects reduces the upward motion and convective clouds in the oceanic regions. The ocean-land transports are linked to the partitioning of surface SH and LH fluxes that increases humidity over lands and enhances deep convection over the tropical lands

Large Magnetoresistance in Compensated Semimetals TaAs2_2 and NbAs2_2

We report large magnetoresistance (MR) at low temperatures in single-crystalline nonmagnetic compounds TaAs$_2$ and NbAs$_2$. Both compounds exhibit parabolic-field-dependent MR larger than $5\times10^3$ in a magnetic field of 9 Tesla at 2 K. The MR starts to deviate from parabolic dependence above 10 T and intends to be saturated in 45 T for TaAs$_2$ at 4.2 K. The Hall resistance measurements and band structural calculations reveal their compensated semimetal characteristics. The large MR at low temperatures is ascribed to a resonance effect of the balanced electrons and holes with large mobilities. We also discuss the relation of the MR and samples' quality for TaAs$_2$ and other semimetals. We found that the magnitudes of MR are strongly dependent on the samples' quality for different compounds.Comment: 26 pages, 11 figures, 2 table

Exotic Superconducting Properties in Topological Nodal Semimetal PbTaSe2_2

We report the electronic properties of superconductivity in the topological nodal-line semimetal PbTaSe$_2$. Angle-resolved photoemission measurements accompanied by band calculations confirmed the nodal-line band structure in the normal state of single crystalline PbTaSe$_2$. Resistivity, magnetic-susceptibility and specific heat measurements have also been performed on high-quality single crystals. We observed upward features and large anisotropy in upper critical field ($H_{c2}$) measured in-plane (H//\textbf{ab}) and out-plane (H//\textbf{c}), respectively. Especially, $H_{c2}$ measured in H//\textbf{ab} shows sudden upward features rather than a signal of saturation in ultralow temperatures. The specific heat measurements under magnetic field reveal a full superconducting gap with no gapless nodes. These behaviors in this clean noncentrosymmetric superconductor is possibly related to the underlying exotic physics, providing important clue for realization of topological superconductivity.Comment: 6 pages, 5 figures,1 table;Accepted for publication on PR