Genetics and Molecular Dynamics of L,L-Diaminopimelate Aminotransferase (DapL): an Enzyme Involved in Lysine and Peptidoglycan Biosynthesis

The marked increase of bacteria that are resistant to clinically relevant antibiotics in recent years has sparked a push in the development and discovery of novel antibiotics. Complementary to this, the identification of novel antibiotic targets is also of great interest. The lysine biosynthesis pathway is an ideal candidate for these efforts because its product is an essential amino acid. Lysine cannot be synthesized by humans and thus poses minimal risk of side effects if synthesis is targeted. The penultimate product in the lysine biosynthesis pathway, meso-DAP, is also a key component of the gram-negative bacterial cell wall peptidoglycan layer. The L,L-diaminopimelate aminotransferase (DapL) pathway, a recently discovered variant in the lysine biosynthetic pathway is especially of interest because it has been identified in only about 13% of bacteria. Because of its narrow distribution in bacteria, it could be an ideal target for the development of narrow spectrum antibiotics. A key enzyme in the pathway, DapL is a homodimer that catalyzes the conversion of tetrahydrodipicolinate (THDP) to L,L-diaminopimelate (L,L-DAP) in a single, reversible transamination reaction. While this enzyme is essential in plants that contain the pathway, it is not directly known whether the same is true for bacteria that contain the pathway. In order to evaluate DapL as a target for the development of narrow spectrum antibiotics, genetic and phenotypic characterizations must be performed. This project evaluated DapL from Verrucomicrobium spinosum, a close relative of Chlamydia, as a potential target in the development of antibiotic compounds. It assessed the essentiality of the VsdapL gene via targeted knockouts using the CRISPR/cas9 system, providing evidence supporting the essentiality of the gene in bacteria. It also evaluated putative antagonistic ligands using a comprehensive and comparative molecular dynamics (MD) software package – DROIDS (Detecting Relative Outlier Impacts in Dynamic Simulations) 2.0, providing insight into the dynamic behavior of the DapL protein and identifying a correlation between total effect on protein dynamics in silico and inhibition measured in vitro

Duality Invariance of Cosmological Perturbation Spectra

I show that cosmological perturbation spectra produced from quantum fluctuations in massless or self-interacting scalar fields during an inflationary era remain invariant under a two parameter family of transformations of the homogeneous background fields. This relates slow-roll inflation models to solutions which may be far from the usual slow-roll limit. For example, a scale-invariant spectrum of perturbations in a minimally coupled, massless field can be produced by an exponential expansion with $a\propto e^{Ht}$, or by a collapsing universe with $a\propto (-t)^{2/3}$.Comment: 5 pages, Latex with Revtex. Hamiltonian formulation added and discussion expanded. Version to appear in Phys Rev

Strings in extremal BTZ black holes

We study the spectrum of the worldsheet theory of the bosonic closed string in the massless and extremal rotating BTZ black holes. We use a hyperbolic Wakimoto representation of the SL(2,R) currents to construct vertex operators for the string modes on these backgrounds. We argue that there are tachyons in the twisted sector, but these are not localised near the horizon. We study the relation to the null orbifold in the limit of vanishing cosmological constant. We also discuss the problem of extending this analysis to the supersymmetric case.Comment: 20 pages, no figure

Late Holocene paleohydrology of Walker Lake and the Carson Sink in the western Great Basin, Nevada, USA

The late Holocene histories of Walker Lake and the Carson Sink were reconstructed by synthesizing existing data in both basins along with new age constraints from key sites, supplemented with paleohydrologic modeling. The repeated diversions of the Walker River to the Carson Sink and then back to Walker Lake caused Walker Lake–level fluctuations spanning ± 50 m. Low lake levels at about 1000, 750, and 300 cal yr BP are time correlative to the ages of fluvial deposits along the Walker River paleochannel, when flow was directed toward the Carson Sink. The timing and duration of large lakes in the Carson Sink were further refined using moisture-sensitive tree-ring chronologies. The largest lakes required a fourfold to fivefold increase in discharge spanning decades. Addition of Walker River flow to the Carson Sink by itself is inadequate to account for the required discharge. Instead, increases in the runoff coefficient and larger areas of the drainage basin contributing surface runoff may explain the enhanced discharge required to create these large lakes

Late Pleistocene to present lake-level fluctuations at Pyramid and Winnemucca lakes, Nevada, USA

A new lake-level curve for Pyramid and Winnemucca lakes, Nevada, is presented that indicates that after the ~15,500 cal yr BP Lake Lahontan high stand (1338 m), lake level fell to an elevation below 1200 m, before rising to 1230 m at the 12,000 cal yr BP Younger Dryas high stand. Lake level then fell to 1155 m by ~10,500 cal yr BP followed by a rise to 1200 m around 8000 cal yr BP. During the mid-Holocene, levels were relatively low (~1155 m) before rising to moderate levels (1190–1195 m) during the Neopluvial period (~4800–3400 cal yr BP). Lake level again plunged to about 1155 m during the late Holocene dry period (~2800–1900 cal yr BP) before rising to about 1190 m by ~1200 cal yr BP. Levels have since fluctuated within the elevation range of about 1170–1182 m except for the last 100 yr of managed river discharge when they dropped to as low as 1153 m. Late Holocene lake-level changes correspond to volume changes between 25 and 55 km3 and surface area changes between 450 and 900 km2. These lake state changes probably encompass the hydrologic variability possible under current climate boundary conditions

Tachyons in Compact Spaces

We discuss condensations of closed string tachyons localized in compact spaces. Time evolution of an on-shell condensation is naturally related to the worldsheet RG flow. Some explicit tachyonic compactifications of Type II string theory is considered, and some of them are shown to decay into supersymmetric theories known as the little string theories.Comment: 14 page

Why does visual working memory ability improve with age : more objects, more feature detail, or both? A registered report

We investigated how visual working memory (WM) develops with age across the early elementary school period (6–7 years), early adolescence (11–13 years), and early adulthood (18–25 years). The work focuses on changes in two parameters: the number of objects retained at least in part, and the amount of feature-detail remembered for such objects. Some evidence suggests that, while infants can remember up to three objects, much like adults, young children only remember around two objects. This curious, nonmonotonic trajectory might be explained by differences in the level of feature-detail required for successful performance in infant versus child/adult memory paradigms. Here, we examined if changes in one of two parameters (the number of objects, and the amount of detail retained for each object) or both of them together can explain the development of visual WM ability as children grow older. To test it, we varied the amount of feature-detail participants need to retain. In the baseline condition, participants saw an array of objects and simply were to indicate whether an object was present in a probed location or not. This phase begun with a titration procedure to adjust each individual's array size to yield about 80% correct. In other conditions, we tested memory of not only location but also additional features of the objects (color, and sometimes also orientation). Our results suggest that capacity growth across ages is expressed by both improved location-memory (whether there was an object in a location) and feature completeness of object representations

Conformationally restricted calpain inhibitors

The cysteine protease calpain-I is linked to several diseases and is therefore a valuable target for inhibition. Selective inhibition of calpain-I has proved difficult as most compounds target the active site and inhibit a broad spectrum of cysteine proteases as well as other calpain isoforms. Selective inhibitors might not only be potential drugs but should act as tools to explore the physiological and pathophysiological roles of calpain-I. α-Mercaptoacrylic acid based calpain inhibitors are potent, cell permeable and selective inhibitors of calpain-I and calpain-II. These inhibitors target the calcium binding domain PEF(S) of calpain-I and -II. Here X-ray diffraction analysis of co-crystals of PEF(S) revealed that the disulfide form of an α-mercaptoacrylic acid bound within a hydrophobic groove that is also targeted by a calpastatin inhibitory region and made a greater number of favourable interactions with the protein than the reduced sulfhydryl form. Measurement of the inhibitory potency of the α-mercaptoacrylic acids and X-ray crystallography revealed that the IC50 values decreased significantly on oxidation as a consequence of the stereo-electronic properties of disulfide bonds that restrict rotation around the S–S bond. Consequently, thioether analogues inhibited calpain-I with potencies similar to those of the free sulfhydryl forms of α-mercaptoacrylic acids

Perturbative Gauge Theory and Closed String Tachyons

We find an interesting connection between perturbative large N gauge theory and closed superstrings. The gauge theory in question is found on N D3-branes placed at the tip of the cone R^6/Gamma. In our previous work we showed that, when the orbifold group Gamma breaks all supersymmetry, then typically the gauge theory is not conformal because of double-trace couplings whose one-loop beta functions do not possess real zeros. In this paper we observe a precise correspondence between the instabilities caused by the flow of these double-trace couplings and the presence of tachyons in the twisted sectors of type IIB theory on orbifolds R^{3,1}x R^6/Gamma. For each twisted sectors that does not contain tachyons, we show that the corresponding double-trace coupling flows to a fixed point and does not cause an instability. However, whenever a twisted sector is tachyonic, we find that the corresponding one-loop beta function does not have a real zero, hence an instability is likely to exist in the gauge theory. We demonstrate explicitly the one-to-one correspondence between the regions of stability/instability in the space of charges under Gamma that arise in the perturbative gauge theory and in the free string theory. Possible implications of this remarkably simple gauge/string correspondence are discussed.Comment: 25 pages, Latex; V2: Clarifications and references adde