Showing 671 - 680 of 733 Items
Metabolic inhibitors of bacterial glycan biosynthesis
Date: 2020-02-21
Creator: Daniel A. Williams, Kabita Pradhan, Ankita Paul, Ilana R. Olin, Owen T., Tuck, Karen D. Moulton, Suvarn S. Kulkarni, Danielle H. Dube
Access: Open access
- The bacterial cell wall is a quintessential drug target due to its critical role in colonization of the host, pathogen survival, and immune evasion. The dense cell wall glycocalyx contains distinctive monosaccharides that are absent from human cells, and proper assembly of monosaccharides into higher-order glycans is critical for bacterial fitness and pathogenesis. However, the systematic study and inhibition of bacterial glycosylation enzymes remains challenging. Bacteria produce glycans containing rare deoxy amino sugars refractory to traditional glycan analysis, complicating the study of bacterial glycans and the creation of glycosylation inhibitors. To ease the study of bacterial glycan function in the absence of detailed structural or enzyme information, we crafted metabolic inhibitors based on rare bacterial monosaccharide scaffolds. Metabolic inhibitors were assessed for their ability to interfere with glycan biosynthesis and fitness in pathogenic and symbiotic bacterial species. Three metabolic inhibitors led to dramatic structural and functional defects in Helicobacter pylori. Strikingly, these inhibitors acted in a bacteria-selective manner. These metabolic inhibitors will provide a platform for systematic study of bacterial glycosylation enzymes not currently possible with existing tools. Moreover, their selectivity will provide a pathway for the development of novel, narrow-spectrum antibiotics to treat infectious disease. Our inhibition approach is general and will expedite the identification of bacterial glycan biosynthesis inhibitors in a range of systems, expanding the glycochemistry toolkit.
Recruiting the Host's Immune System to Target Helicobacter pylori's Surface Glycans
Date: 2013-04-01
Creator: Pornchai Kaewsapsak, Onyinyechi Esonu, Danielle H. Dube
Access: Open access
- Due to the increased prevalence of bacterial strains that are resistant to existing antibiotics, there is an urgent need for new antibacterial strategies. Bacterial glycans are an attractive target for new treatments, as they are frequently linked to pathogenesis and contain distinctive structures that are absent in humans. We set out to develop a novel targeting strategy based on surface glycans present on the gastric pathogen Helicobacter pylori (Hp). In this study, metabolic labeling of bacterial glycans with an azide-containing sugar allowed selective delivery of immune stimulants to azide-covered Hp. We established that Hp's surface glycans are labeled by treatment with the metabolic substrate peracetylated N-azidoacetylglucosamine (Ac4GlcNAz). By contrast, mammalian cells treated with Ac4GlcNAz exhibited no incorporation of the chemical label within extracellular glycans. We further demonstrated that the Staudinger ligation between azides and phosphines proceeds under acidic conditions with only a small loss of efficiency. We then targeted azide-covered Hp with phosphines conjugated to the immune stimulant 2,4-dinitrophenyl (DNP), a compound capable of directing a host immune response against these cells. Finally, we report that immune effector cells catalyze selective damage in vitro to DNP-covered Hp in the presence of anti-DNP antibodies. The technology reported herein represents a novel strategy to target Hp based on its glycans. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Spatial heterogeneity and environmental predictors of permafrost region soil organic carbon stocks
Date: 2021-02-24
Creator: Umakant Mishra, Gustaf Hugelius, Eitan Shelef, Yuanhe Yang, Jens, Strauss, Alexey Lupachev, Jennifer W. Harden, Julie D. Jastrow, Chien Lu Ping, William J. Riley, Edward A.G. Schuur, Roser Matamala, Matthias Siewert, Lucas E. Nave, Charles D. Koven, Matthias Fuchs
Access: Open access
- Large stocks of soil organic carbon (SOC) have accumulated in the Northern Hemisphere permafrost region, but their current amounts and future fate remain uncertain. By analyzing dataset combining >2700 soil profiles with environmental variables in a geospatial framework, we generated spatially explicit estimates of permafrost-region SOC stocks, quantified spatial heterogeneity, and identified key environmental predictors. We estimated that Pg C are stored in the top 3 m of permafrost region soils. The greatest uncertainties occurred in circumpolar toe-slope positions and in flat areas of the Tibetan region. We found that soil wetness index and elevation are the dominant topographic controllers and surface air temperature (circumpolar region) and precipitation (Tibetan region) are significant climatic controllers of SOC stocks. Our results provide first high-resolution geospatial assessment of permafrost region SOC stocks and their relationships with environmental factors, which are crucial for modeling the response of permafrost affected soils to changing climate.
Genomic plasticity of the human fungal pathogen Candida albicans
Date: 2010-07-01
Creator: Anna Selmecki, Anja Forche, Judith Berman
Access: Open access
- The genomic plasticity of Candida albicans, a commensal and common opportunistic fungal pathogen, continues to reveal unexpected surprises. Once thought to be asexual, we now know that the organism can generate genetic diversity through several mechanisms, including mating between cells of the opposite or of the same mating type and by a parasexual reduction in chromosome number that can be accompanied by recombination events (2, 12, 14, 53, 77, 115). In addition, dramatic genome changes can appear quite rapidly in mitotic cells propagated in vitro as well as in vivo. The detection of aneuploidy in other fungal pathogens isolated directly from patients (145) and from environmental samples (71) suggests that variations in chromosome organization and copy number are a common mechanism used by pathogenic fungi to rapidly generate diversity in response to stressful growth conditions, including, but not limited to, antifungal drug exposure. Since cancer cells often become polyploid and/or aneuploid, some of the lessons learned from studies of genome plasticity in C. albicans may provide important insights into how these processes occur in higher-eukaryotic cells exposed to stresses such as anticancer drugs. © 2010, American Society for Microbiology.
Initial experiments in using communication swarms to improve the performance of swarm systems
Date: 2012-01-01
Creator: Stephen M. Majercik
Access: Open access
- Swarm intelligence can provide robust, adaptable, scalable solutions to difficult problems. The distributed nature of swarm activity is the basis of these desirable qualities, but it also prevents swarm-based techniques from having direct access to global knowledge that could facilitate the task at hand. Our experiments indicate that a swarm system can use an auxiliary swarm, called a communication swarm, to create and distribute an approximation of useful global knowledge, without sacrificing robustness, adaptability, and scalability. We describe a communication swarm and validate its effectiveness on a simple problem.
Quantitative estimation of localization errors of 3 d transition metal pseudopotentials in diffusion Monte Carlo
Date: 2017-07-14
Creator: Allison L. Dzubak, Jaron T. Krogel, Fernando A. Reboredo
Access: Open access
- The necessarily approximate evaluation of non-local pseudopotentials in diffusion Monte Carlo (DMC) introduces localization errors. We estimate these errors for two families of non-local pseudopotentials for the first-row transition metal atoms Sc-Zn using an extrapolation scheme and multideterminant wavefunctions. Sensitivities of the error in the DMC energies to the Jastrow factor are used to estimate the quality of two sets of pseudopotentials with respect to locality error reduction. The locality approximation and T-moves scheme are also compared for accuracy of total energies. After estimating the removal of the locality and T-moves errors, we present the range of fixed-node energies between a single determinant description and a full valence multideterminant complete active space expansion. The results for these pseudopotentials agree with previous findings that the locality approximation is less sensitive to changes in the Jastrow than T-moves yielding more accurate total energies, however not necessarily more accurate energy differences. For both the locality approximation and T-moves, we find decreasing Jastrow sensitivity moving left to right across the series Sc-Zn. The recently generated pseudopotentials of Krogel et al. [Phys. Rev. B 93, 075143 (2016)] reduce the magnitude of the locality error compared with the pseudopotentials of Burkatzki et al. [J. Chem. Phys. 129, 164115 (2008)] by an average estimated 40% using the locality approximation. The estimated locality error is equivalent for both sets of pseudopotentials when T-moves is used. For the Sc-Zn atomic series with these pseudopotentials, and using up to three-body Jastrow factors, our results suggest that the fixed-node error is dominant over the locality error when a single determinant is used.
Correction: CO2 induced phase transitions in diamine-appended metal-organic frameworks (Chemical Science (2015) 6 (5177-5185) DOI: 10.1039/c5sc01828e)
Date: 2019-01-01
Creator: Bess Vlaisavljevich, Sondre K. Schnell, Allison L. Dzubak, Kyuho Lee, Nora, Planas, Jeffrey B. Neaton, Laura Gagliardi, Berend Smit
Access: Open access
- The authors regret that there are some discrepancies reproducing the data in the original article due to the determined coordinates not being the fully optimised geometries. The authors have provided more information as follows. In the manuscript entitled 'CO2 induced phase transitions in diamine-appended metal-organic frameworks', minor errors with the attached coordinates and energies reported in the paper have recently been identified. In this communication, we correct these errors. Here, we present updated optimized geometries and binding energies. We also take this opportunity to include an extended computational details section to ensure reproducibility. In addition, we show that the overall conclusions of the paper are not affected by these changes. A detailed comparison with the results reported by Lee et al.1 revealed that the DFT optimization of the coordinates provided with the manuscript do not lead to the values reported in the manuscript, and they warrant correction. Corrected coordinates and updated tables (Tables 1-7) and figures (Fig. 1, 2, 4 and 5) are included here for calculations using the PBE functional. These structures have been repeated using a slightly tighter force threshold than in the original manuscript (details below). The M06-L calculations reported in the original manuscript are not revisited since they were performed to assess the role of dispersion. Since the publication of our work in 2015, a far more detailed study of this effect has been published by one of the authors rendering these M06-L calculations unnecessary and we refer readers interested in the role of dispersion on the carbamate formation to this more recent study by Lee et al.1 In addition to correcting our DFT calculations, we examine the effects of the revised DFT values on the lattice model in this work.We recompute the lattice model with the M06-L and PBE values fromthe original manuscript as well as the corrected PBE values reported below (Fig. 6-8 and Tables 8-10). In all three sets of isotherm plots the ordering is preserved but the inflection points are spaced differently with the new PBE numbers, leading to quantitative differences that are nonetheless qualitatively similar to previous work. Finally, we discuss different ways that CO2 can coordinate to the metal binding site, as shown in Fig. 3. We should have notedmore clearly in ourmanuscript that these were starting configurations and not necessarily the final converged structures since our goal was to try several starting geometries to determine which coordination environment around the metal site was lowest in energy. Take for example bidentate insertion. Chemical intuition suggests that this structure could rotate to one that has only one CO2 oxygen center closer to the metal than the other and we observe this in our optimized structure. The resulting geometries we obtained for the starting arrangements noted in the figure are higher in energy than the chain model as reported in our original paper.We wish to emphasize that at the time of our 2015 study, our objective was to understand whether or not CO2 was bound to the metal and if one-dimensional chain formation could lead to a step in the adsorption isotherm. It has since become clear that a far more thorough study of the arrangements of the amines is required to truly understand competing amine arrangements preset in experiment. This was outside the scope of our work. Once more, these calculations are perhaps now outdated given work in the field in recent years. We again refer interested readers to a more recent study by Lee et al.1 1. Extended computational details to ensure reproducibility In the course of rectifying the error in our calculations, we wanted to ensure that all revised calculations were converged using the exact same protocol; therefore, we repeated the PBE calculations for the pair and chain models using updated computational details given here to ensure reproducibility. The M2(dobpdc) MOF contains six unsaturated metal sites per unit cell. To calculate the binding energies of CO2 in its amine appended analogue mmen-M2(dobpdc), one mmen ligand per CO2 was added per unit cell. The smaller sized ethylenediamine (en) was used to saturate the remaining amines not involved in CO2 binding. In the case of the pair mode, two mmen-amines are included per unit cell only. All DFT calculations were performed with periodic boundary conditions carried out using the VASP 5.4.4 package (original calculations were performed with VASP 5.3.3). The PBE functional was employed to examine the energetics of CO2 adsorption.3 On-site Hubbard U corrections were employed for metal d electrons.4 The U values are determined to reproduce oxidation energies in the respective metal oxides and are given in the tables below. The electron-ion interactions in these calculations were described with the projector augmented wave (PAW) method developed by Blöchl with an energy cutoff of 550 eV.5 This combination of the PBE functional, PAW scheme, and energy cutoff was used for full geometry optimization of the various species investigated until the forces on all atoms were smaller than 0.02 eV Å-1 and the SCF convergence was set to 1 × 10-7 eV. Given the large size of the unit cell and the tests with other numbers of K-points from the original study, only results obtained from G-point calculations are reported here. Finally, heats of adsorption are now reported below along with E + ZPE values, while in the original manuscript only E + ZPE were reported. No changes were made to how the vibrational corrections were computed; however, we have included some additional details to ensure reproducibility.6 Harmonic vibrational modes (ωi) were computed for CO2 in the gas phase and its bound product state (amine-CO2-MOF complex). The framework itself was taken to be rigid and only the vibrational modes associated with the motion of the amine, the metal center, first coordination sphere (oxygen atoms bound to the metal in the MOF backbone), and (if present) the bound CO2 were computed. Since the harmonic approximation breaks down for low frequency modes, we replaced all modes less than 50 cm-1 with 50 cm-1 when computing the zero-point and thermal energies. The following standard harmonic expressions were used to compute the vibrational corrections: Zero-point vibrational energy (ZPE) is: [Equation presented here] While for the bound product, the rotational and translational degrees of freedom of CO2 have been converted to additional vibrational modes allowing one to compute the thermal correction simply as: [Equation presented here] 2. Values for the chain model The chain model used in our original study included 1 mmen- and 5 en-amines. The values from the original paper are reported in Table 1. When we repeat these calculations using the procedure described in Section 1, we obtain the values in Table 2. In addition to the chain model described above (1 mmen- and 5 en-amines per unit cell), during our original study we performed calculations with another model that was not included in the manuscript since its values yielded results further from experiment. This model includes only 1 mmen-amine per unit cell (no other amines) and was used to test the assumption that the five enamines are indeed spectators with respect to the metal dependence of the binding energy. We present the results from this model in Table 3. In the original paper we noted that the energy and bond length trends are correlated and are consistent with the Irving-Williams series. This is no longer true for all metals under investigation, with Zn being an outlier. The results for Zn can be explained by more recent work.1 3. Values for the pair model The model used to compute the "pair" adsorption mechanisms included 2 mmen-amines and 0 en-amines. The values in the original paper are presented in Table 5. 4. Lattice model plots The lattice models to generate adsorption isotherms for these systems were run at one temperature (∼25 °C) using four different input parameters. First the M06-L and PBE values from the original paper were used once more as it has been some time since we have run the lattice model. Then the model is repeated with the new set of values from PBE. If we compare Fig. 7 and 8, the order is preserved, but the infliction points are spaced a bit differently. This is due to the scaling factor being constant and is something we scaled for each of the different systems as well. The slope is also a bit different, but not more then we should expect for this simple lattice model. Furthermore, we only ever aimed to reproduce the step and the order of the metals. Any finer details cannot be expected to be obtained from this model. The exact values used to compute the isotherms are given in the tables below. The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.
Characterizing the influence of Atlantic water intrusion on water mass formation and phytoplankton distribution in Kongsfjorden, Svalbard
Date: 2019-12-01
Creator: Courtney M. Payne, Collin S. Roesler
Access: Open access
- Warm water intrusion into Arctic fjords is increasingly affecting polar ecosystems. This study investigated how Atlantic water intrusion and tidewater glacial melting impacted water mass formation and phytoplankton distribution in Kongsfjorden, Svalbard. Field data were collected over a 2-week period during the height of the melt season in August 2014 and were contextualized within an 18-year regional MODIS satellite record. Since 1998, intruding waters have warmed by 4–5.5 °C, which has prevented sea ice formation and changed the characteristics of fjord bottom waters. Modeled light fields suggest that suspended sediment in this glacial meltwater has reduced the euphotic zone close to the ice face, contributing to lower phytoplankton concentrations in both persistent and intermittently sediment-laden meltwater plumes. However, measurements collected close to terrestrially terminating glaciers indicate that turbidity is significantly lower in the meltwater plumes, resulting in deep euphotic zones and high phytoplankton concentrations. The results of this study support a three-part conceptual model of the effects of warm-water intrusion on water mass formation and primary production within 10 km of tidewater glaciers. Initially, warm water intrusion reduces sea ice coverage, which increases the euphotic depth and increases phytoplankton biomass. Warm water intrusions may also result in increased melting of tidewater glaciers, enhanced sediment release, reduction in euphotic depth and reduction in phytoplankton biomass. Ultimately, as tidewater glaciers retreat and become terrestrially terminating, the sediment load decreases, the euphotic zone again increases, and phytoplankton biomass increases.
Reviews fall 2019-Special issue on Bauhaus centenary
Date: 2019-01-01
Creator: Kathleen James-Chakraborty, Pep Avilés, Claudia Tittel, Jill Pearlman
Access: Open access
Brain Networks Related to Beta Oscillatory Activityduring Episodic Memory Retrieval
Date: 2018-02-01
Creator: Erika Nyhus
Access: Open access
- Evidence from fMRI has consistently located a widespread network of frontal, parietal, and temporal lobe regions during episodic retrieval. However, the temporal limitations of the fMRI methodology have made it difficult to assess the transient network dynamics by which these distributed regions coordinate activity. Recent evidence suggests that beta oscillations (17-20 Hz) are important for top-down control for memory suppression. However, the spatial limitations of the EEG methodology make it difficult to assess the relationship between these oscillatory signals and the distributed networks identified with fMRI. This study used simultaneous EEG/fMRI to identify networks related to beta oscillations during episodic retrieval. Participants studied adjectives and either imagined a scene (Place Task) or judged its pleasantness (Pleasant Task). During the recognition test, participants decided which task was performed with each word (“Old Place Task” or “Old Pleasant Task”) or “New.” EEG results revealed that posterior beta power was greater for new than old words. fMRI results revealed activity in a frontal, parietal network that was greater for old than new words, consistent with prior studies. Although overall beta power increases correlated with decreased activity within a predominantly parietal network, within the right dorsolateral and ventrolateral pFC, beta power correlated with BOLD activity more under conditions requiring more cognitive control and EEG/fMRI effects in the right frontal cortex correlated with BOLD activity in a frontoparietal network. Therefore, using simultaneous EEG and fMRI, the present results suggest that beta oscillations are related to postretrieval control operations in the right frontal cortex and act within a broader postretrieval control network. © 2017 Massachusetts Institute of Technology.