Reinterpretation and Long-Term Preservation of Data and Code

Careful preservation of experimental data, simulations, analysis products, and theoretical work maximizes their long-term scientific return on investment by enabling new analyses and reinterpretation of the results in the future. Key infrastructure and technical developments needed for some high-value science targets are not in scope for the operations program of the large experiments and are often not effectively funded. Increasingly, the science goals of our projects require contributions that span the boundaries between individual experiments and surveys, and between the theoretical and experimental communities. Furthermore, the computational requirements and technical sophistication of this work is increasing. As a result, it is imperative that the funding agencies create programs that can devote significant resources to these efforts outside of the context of the operations of individual major experiments, including smaller experiments and theory/simulation work. In this Snowmass 2021 Computational Frontier topical group report (CompF7: Reinterpretation and long-term preservation of data and code), we summarize the current state of the field and make recommendations for the future.Comment: Snowmass 2021 Computational Frontier CompF7 Reinterpretation and long-term preservation of data and code topical group repor

Identification of a 1-deoxy-D-xylulose-5-phosphate synthase (DXS) mutant with improved crystallographic properties

In this report, we describe a truncated Deinococcus radiodurans 1-deoxy-D-xylulose-5-phosphate synthase (DXS) protein that retains enzymatic activity, while slowing protein degradation and showing improved crystallization properties. With modern drug-design approaches relying heavily on the elucidation of atomic interactions of potential new drugs with their targets, the need for co-crystal structures with the compounds of interest is high. DXS itself is a promising drug target, as it catalyzes the first reaction in the 2-C-methyl-D-erythritol 4-phosphate (MEP)-pathway for the biosynthesis of the universal precursors of terpenes, which are essential secondary metabolites. In contrast to many bacteria and pathogens, which employ the MEP pathway, mammals use the distinct mevalonate-pathway for the biosynthesis of these precursors, which makes all enzymes of the MEP-pathway potential new targets for the development of anti-infectives. However, crystallization of DXS has proven to be challenging: while the first X-ray structures from Escherichia coli and D. radiodurans were solved in 2004, since then only two additions have been made in 2019 that were obtained under anoxic conditions. The presented site of truncation can potentially also be transferred to other homologues, opening up the possibility for the determination of crystal structures from pathogenic species, which until now could not be crystallized. This manuscript also provides a further example that truncation of a variable region of a protein can lead to improved structural data

Galaxy and Mass Assembly (GAMA): The stellar mass budget of galaxy spheroids and discs

We build on a recent photometric decomposition analysis of 7506 Galaxy and Mass Assembly (GAMA) survey galaxies to derive stellar mass function fits to individual spheroid and disc component populations down to a lower mass limit of log(M*/M⊙) = 8. We find that the spheroid/disc mass distributions for individual galaxy morphological types are well described by single Schechter function forms. We derive estimates of the total stellar mass densities in spheroids (ρspheroid = 1.24 ± 0.49 × 108 M⊙ Mpc −3h0.7) and discs (ρdisc = 1.20 ± 0.45 × 108 M⊙ Mpc −3h0.7), which translates to approximately 50 per cent of the local stellar mass density in spheroids and 48 per cent in discs. The remaining stellar mass is found in the dwarf ‘little blue spheroid’ class, which is not obviously similar in structure to either classical spheroid or disc populations. We also examine the variation of component mass ratios across galaxy mass and group halo mass regimes, finding the transition from spheroid to disc mass dominance occurs near galaxy stellar mass ∼1011 M⊙ and group halo mass ∼1012.5 M⊙h−1. We further quantify the variation in spheroid-to-total mass ratio with group halo mass for central and satellite populations as well as the radial variation of this ratio within groups

First crystal structures of 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization

The development of drug resistance by Mycobacterium tuberculosis and other pathogenic bacteria emphasizes the need for new antibiotics. Unlike animals, most bacteria synthesize isoprenoid precursors through the MEP pathway. 1-Deoxy-d-xylulose 5-phosphate synthase (DXPS) catalyzes the frst reaction of the MEP pathway and is an attractive target for the development of new antibiotics. We report here the successful use of a loop truncation to crystallize and solve the frst DXPS structures of a pathogen, namely M. tuberculosis (MtDXPS). The main diference found to other DXPS structures is in the active site where a highly coordinated water was found, showing a new mechanism for the enamine-intermediate stabilization. Unlike other DXPS structures, a “fork-like” motif could be identifed in the enamine structure, using a diferent residue for the interaction with the cofactor, potentially leading to a decrease in the stability of the intermediate. In addition, electron density suggesting a phosphate group could be found close to the active site, provides new evidence for the D-GAP binding site. These results provide the opportunity to improve or develop new inhibitors specifc for MtDXPS through structure-based drug design

First crystal structures of 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization

The development of drug resistance by Mycobacterium tuberculosis and other pathogenic bacteria emphasizes the need for new antibiotics. Unlike animals, most bacteria synthesize isoprenoid precursors through the MEP pathway. 1-Deoxy-D-xylulose 5-phosphate synthase (DXPS) catalyzes the first reaction of the MEP pathway and is an attractive target for the development of new antibiotics. We report here the successful use of a loop truncation to crystallize and solve the first DXPS structures of a pathogen, namely M. tuberculosis (MtDXPS). The main difference found to other DXPS structures is in the active site where a highly coordinated water was found, showing a new mechanism for the enamine-intermediate stabilization. Unlike other DXPS structures, a "fork-like" motif could be identified in the enamine structure, using a different residue for the interaction with the cofactor, potentially leading to a decrease in the stability of the intermediate. In addition, electron density suggesting a phosphate group could be found close to the active site, provides new evidence for the D-GAP binding site. These results provide the opportunity to improve or develop new inhibitors specific for MtDXPS through structure-based drug design

Cold heteromolecular dipolar collisions

We present the first experimental observation of cold collisions between two different species of neutral polar molecules, each prepared in a single internal quantum state. Combining for the first time the techniques of Stark deceleration, magnetic trapping, and cryogenic buffer gas cooling allows the enhancement of molecular interaction time by 10$^5$. This has enabled an absolute measurement of the total trap loss cross sections between OH and ND$_3$ at a mean collision energy of 3.6 cm$^{-1}$ (5 K). Due to the dipolar interaction, the total cross section increases upon application of an external polarizing electric field. Cross sections computed from \emph{ab initio} potential energy surfaces are in excellent agreement with the measured value at zero external electric field. The theory presented here represents the first such analysis of collisions between a $^2\Pi$ radical and a closed-shell polyatomic molecule.Comment: 7 pages, 5 figure

Pediculosis and the Pediatrician

Head lice commonly evoke feelings of disgust, revulsion, anger, and shame among parents and patients. There should, however, be no great cause for such alarm if a physician suspects pediculosis capitis. The recent introduction of several new pediculicidal drugs now allows a choice among four distinct therapeutic agents, which should substantially improve control of isolated cases and epidemics. Physicians must be aware that consumer groups are pressing public health authorities and drug manufacturers to establish proper treatment standards and safety warnings for the use of these agents. In addition, some controversy surrounds the use of lindane in children. This paper reviews the epidemiology and clinical appearance of pediculosis capitis in children, with emphasis on these recent developments. Pubic lice ( Phthirus pubis ) and body lice ( Pedicutus humanus corporis ), both of which are much less common pediatric infestations, are mentioned only briefly.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72607/1/j.1525-1470.1984.tb00447.x.pd

Galaxy and Mass Assembly (GAMA): the stellar mass budget of galaxy spheroids and discs

We build on a recent photometric decomposition analysis of 7506 Galaxy and Mass Assembly (GAMA) survey galaxies to derive stellar mass function fits to individual spheroid and disc component populations down to a lower mass limit of log(M*/M⊙) = 8. We find that the spheroid/disc mass distributions for individual galaxy morphological types are well described by single Schechter function forms. We derive estimates of the total stellar mass densities in spheroids (ρspheroid = 1.24 ± 0.49 × 108 M⊙ Mpc -3h0.7) and discs (ρdisc = 1.20 ± 0.45 × 108 M⊙ Mpc -3h0.7), which translates to approximately 50 per cent of the local stellar mass density in spheroids and 48 per cent in discs. The remaining stellar mass is found in the dwarf 'little blue spheroid' class, which is not obviously similar in structure to either classical spheroid or disc populations. We also examine the variation of component mass ratios across galaxy mass and group halo mass regimes, finding the transition from spheroid to disc mass dominance occurs near galaxy stellar mass ~1011 M⊙ and group halo mass ~1012.5 M⊙h-1. We further quantify the variation in spheroid-to-total mass ratio with group halo mass for central and satellite populations as well as the radial variation of this ratio within groups.Publisher PDFPeer reviewe

Signatures of Short Distance Physics in the Cosmic Microwave Background

We systematically investigate the effect of short distance physics on the spectrum of temperature anistropies in the Cosmic Microwave Background produced during inflation. We present a general argument-assuming only low energy locality-that the size of such effects are of order H^2/M^2, where H is the Hubble parameter during inflation, and M is the scale of the high energy physics. We evaluate the strength of such effects in a number of specific string and M theory models. In weakly coupled field theory and string theory models, the effects are far too small to be observed. In phenomenologically attractive Horava-Witten compactifications, the effects are much larger but still unobservable. In certain M theory models, for which the fundamental Planck scale is several orders of magnitude below the conventional scale of grand unification, the effects may be on the threshold of detectability. However, observations of both the scalar and tensor fluctuation contributions to the Cosmic Microwave Background power spectrum-with a precision near the cosmic variance limit-are necessary in order to unambiguously demonstrate the existence of these signatures of high energy physics. This is a formidable experimental challenge.Comment: 49 pages, 2 figures. References added, minor typos correcte