The antimicrobial polymer PHMB enters cells and selectively condenses bacterial chromosomes

To combat infection and antimicrobial resistance, it is helpful to elucidate drug mechanism(s) of action. Here we examined how the widely used antimicrobial polyhexamethylene biguanide (PHMB) kills bacteria selectively over host cells. Contrary to the accepted model of microbial membrane disruption by PHMB, we observed cell entry into a range of bacterial species, and treated bacteria displayed cell division arrest and chromosome condensation, suggesting DNA binding as an alternative antimicrobial mechanism. A DNA-level mechanism was confirmed by observations that PHMB formed nanoparticles when mixed with isolated bacterial chromosomal DNA and its effects on growth were suppressed by pairwise combination with the DNA binding ligand Hoechst 33258. PHMB also entered mammalian cells, but was trapped within endosomes and excluded from nuclei. Therefore, PHMB displays differential access to bacterial and mammalian cellular DNA and selectively binds and condenses bacterial chromosomes. Because acquired resistance to PHMB has not been reported, selective chromosome condensation provides an unanticipated paradigm for antimicrobial action that may not succumb to resistance

Melting Himalayan Glaciers Threaten Domestic Water Resources in the Mount Everest Region, Nepal

Retreating glaciers and snowpack loss threaten high-altitude communities that rely upon seasonal melt for domestic water resources. But the extent to which such communities are vulnerable is not yet understood, largely because melt contribution to water supplies is rarely quantified at the catchment scale. The Khumbu Valley, Nepal is a highly glaciated catchment with elevations ranging from 2,000 to 8,848 m above sea level, where more than 80% of annual precipitation falls during the summer monsoon from June to September. Samples were collected from the rivers, tributaries, springs, and taps along the major trekking route between Lukla and Everest Base Camp in the pre-monsoon seasons of 2016–2017. Sources were chosen based upon their use by the communities for drinking, cooking, bathing, and washing, so the sample suite is representative of the local domestic water supply. In addition, meltwater samples were collected directly from the base of the Khumbu Glacier, and several rain samples were collected throughout the study site. Meltwater contribution was estimated from δ18O isotopic data using a two-component mixing model with the Khumbu glacial melt and pre-monsoon rain as endmembers. Results indicate between 34 and 90% of water comes from melt during the dry, pre-monsoon season, with an average meltwater contribution of 65%. With as much as two-thirds of the dry-season domestic water supply at risk, the communities of the Khumbu Valley are extremely vulnerable to the effects of climate change as glaciers retreat and snowpack declines

Estimating Nuisance Parameters in Inverse Problems

Many inverse problems include nuisance parameters which, while not of direct interest, are required to recover primary parameters. Structure present in these problems allows efficient optimization strategies - a well known example is variable projection, where nonlinear least squares problems which are linear in some parameters can be very efficiently optimized. In this paper, we extend the idea of projecting out a subset over the variables to a broad class of maximum likelihood (ML) and maximum a posteriori likelihood (MAP) problems with nuisance parameters, such as variance or degrees of freedom. As a result, we are able to incorporate nuisance parameter estimation into large-scale constrained and unconstrained inverse problem formulations. We apply the approach to a variety of problems, including estimation of unknown variance parameters in the Gaussian model, degree of freedom (d.o.f.) parameter estimation in the context of robust inverse problems, automatic calibration, and optimal experimental design. Using numerical examples, we demonstrate improvement in recovery of primary parameters for several large- scale inverse problems. The proposed approach is compatible with a wide variety of algorithms and formulations, and its implementation requires only minor modifications to existing algorithms.Comment: 16 pages, 5 figure

Hypotheses for the Origin of the Hypanis Fan-Shaped Deposit at the Edge of the Chryse Escarpment, Mars: Is it a Delta?

We investigated the origin of the fan-shaped deposit at the end of Hypanis Valles that has previously been proposed as an ExoMars, Mars 2020, and human mission candidate landing site, and found evidence that the landform is an ancient delta. Previous work suggests that the deposit originated from a time of fluvial activity both distinct from and prior to catastrophic outflow, and crater counting placed the deposit’s age at  ≥ 3.6 Ga. We found over 30 thin sedimentary strata in the proposed delta wall, and from our slope analysis conclude that the fluvial sequence is consistent with a lowering/retreating shoreline. We measured nearly horizontal bedding dip angles ranging from 0° to 2° over long stretches of cliff and bench exposures seen in HiRISE images and HiRISE stereo DTMs. From THEMIS night IR images we determined that the fan-shaped deposit has a low thermal inertia (150-240 Jm-2 K-1 s-1/2) and the surrounding darker-toned units correspond to thermal inertia values as high as 270-390 Jm-2 K-1 s-1/2. We interpret these findings to indicate that the fan-shaped deposit consists mostly of silt-sized and possibly finer grains, and that the extremely low grade and large lateral extent of these beds implies that the depositional environment was calm and relatively long-lived. We interpret the geomorphology and composition as incompatible with an alluvial fan or mudflow hypothesis. From our stratigraphic mapping we interpret the order of events which shaped the region. After the Chryse impact, sediment filled the basin, a confined lake or sea formed allowing a large delta to be deposited near its shoreline, the water level receded to the north, darker sedimentary/volcanic units covered the region and capped the light-toned deposit as hydro-volcanic eruptions shaped the interior of Lederberg crater, freeze/thaw cycles and desiccation induced local fracturing, and finally wrinkle ridges associated with rounded cones warped the landscape following trends in degraded crater rims and existing tectonic features. The ancient deltaic deposit we observe today was largely untouched by subsequent catastrophic outflows, and its surface has been only moderately reshaped by over 3 billion years of aeolian erosion

MatryODShka: Real-time 6DoF Video View Synthesis using Multi-Sphere Images

We introduce a method to convert stereo 360{\deg} (omnidirectional stereo) imagery into a layered, multi-sphere image representation for six degree-of-freedom (6DoF) rendering. Stereo 360{\deg} imagery can be captured from multi-camera systems for virtual reality (VR), but lacks motion parallax and correct-in-all-directions disparity cues. Together, these can quickly lead to VR sickness when viewing content. One solution is to try and generate a format suitable for 6DoF rendering, such as by estimating depth. However, this raises questions as to how to handle disoccluded regions in dynamic scenes. Our approach is to simultaneously learn depth and disocclusions via a multi-sphere image representation, which can be rendered with correct 6DoF disparity and motion parallax in VR. This significantly improves comfort for the viewer, and can be inferred and rendered in real time on modern GPU hardware. Together, these move towards making VR video a more comfortable immersive medium.Comment: 25 pages, 13 figures, Published at European Conference on Computer Vision (ECCV 2020), Project Page: http://visual.cs.brown.edu/matryodshk

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd

An Adaptation to Low Copper in Candida albicans Involving SOD Enzymes and the Alternative Oxidase.

In eukaryotes, the Cu/Zn superoxide dismutase (SOD1) is a major cytosolic cuproprotein with a small fraction residing in the mitochondrial intermembrane space (IMS) to protect against respiratory superoxide. Curiously, the opportunistic human fungal pathogen Candida albicans is predicted to express two cytosolic SODs including Cu/Zn containing SOD1 and manganese containing SOD3. As part of a copper starvation response, C. albicans represses SOD1 and induces the non-copper alternative SOD3. While both SOD1 and SOD3 are predicted to exist in the same cytosolic compartment, their potential role in mitochondrial oxidative stress had yet to be investigated. We show here that under copper replete conditions, a fraction of the Cu/Zn containing SOD1 localizes to the mitochondrial IMS to guard against mitochondrial superoxide. However in copper starved cells, localization of the manganese containing SOD3 is restricted to the cytosol leaving the mitochondrial IMS devoid of SOD. We observe that during copper starvation, an alternative oxidase (AOX) form of respiration is induced that is not coupled to ATP synthesis but maintains mitochondrial superoxide at low levels even in the absence of IMS SOD. Surprisingly, the copper-dependent cytochrome c oxidase (COX) form of respiration remains high with copper starvation. We provide evidence that repression of SOD1 during copper limitation serves to spare copper for COX and maintain COX respiration. Overall, the complex copper starvation response of C. albicans involving SOD1, SOD3 and AOX minimizes mitochondrial oxidative damage whilst maximizing COX respiration essential for fungal pathogenesis

A fraction of <i>C</i>. <i>albicans</i> SOD1 but not SOD3 localizes to the mitochondria IMS.

<p><i>C</i>. <i>albicans</i> strain CAIF-100 was grown in enriched medium in either the presence or absence of 800 μM of the extracellular Cu(I) chelator BCS as indicated. (A) Lysates were prepared from spheroplasts and were analyzed for SOD1 and SOD3 by immunoblot. (B) Total cellular copper was measured by atomic absorption spectroscopy. (C-D) Spheroplast cell lysates (Total) were fractionated into the largely cytosolic post-mitochondrial supernatant (PMS) and crude mitochondria (mito) by differential centrifugation. 70 μg of total lysate protein and the same cell equivalents of PMS and mitochondria were analyzed by immunoblot for SOD2 (marker of mitochondrial matrix), PGK1 (marker of cytosol) and either SOD1 (C) or SOD3 (D). MW = molecular weight markers. SOD1 often appears as two bands, both of which are down-regulated by copper starvation.</p

Effect of inhibiting AOX respiration on mitochondrial superoxide under copper starvation.

<p>MitoSOX Red fluorescence was measured in the designated strains. Where indicated, cells were treated with 5 mM SHAM for 1 hour to inhibit AOX respiration prior to MitoSOX Red incubation. Results represent the averages of two independent cultures with error bars representing standard deviation.</p