987 research outputs found
Investigating Conserved Structure-Function Relationships and Mechanistic Aspects of Sufs, a Type II Cysteine Desulfurase.
No full textElectronic Thesis or DissertationOwing to the use of iron-sulfur clusters in essential biological processes, proper function of cluster biogenesis pathways is crucial for all living organisms. A molecular level understanding of these complex, multi-protein machineries can provide a foundation for the development of therapeutics that can target biogenesis pathways in pathogenic bacteria or treatments for diseases caused by the defects in the pathway, such as Friedreich’s ataxia. Iron-sulfur cluster biogenesis in all domains of life is initiated by the mobilization of sulfur from L-cysteine by enzymes known as cysteine desulfurases. SufS is a type II cysteine desulfurase that initiates iron-sulfur cluster biogenesis in the SUF pathway in E. coli. Like all cysteine desulfurases, SufS is a homodimeric, PLP-dependent enzyme that yields an enzyme bound-persulfide and alanine from L-cysteine. As a type II cysteine desulfurase, SufS requires an accessory protein, SufE, to transfer the persulfide to the downstream targets. Adding to the significant work that has contributed towards our understanding of SufS, the investigations discussed herein are aimed specifically towards probing the conserved regulatory and mechanistic features of SufS that contribute to its catalysis and interactions with SufE. Through the work presented here, we were able to validate the role of a conserved beta-latch motif as a regulatory feature of SufS. A two-step binding model for SufS-SufE complex was established, with the beta-latch motif acting as a regulatory feature in guiding the S-transfer loop in a close approach conformation of SufS-SufE complex for efficient persulfide transfer. Additionally, a coordinated mechanism for the function of conserved residues R56 and R359 is proposed, where R359 governs the positioning of the α3-α4 SufS loop containing the R56 residue that, in turn, modulates SufS catalysis and SufS-SufE binding interactions. Studies on the mechanisms of SufS-SufE complex formation are complemented by an in-depth investigation of the SufS catalytic mechanism utilizing pre-steady state and single-turnover kinetic analysis. This transient kinetic data is consistent with SufS following a half-sites kinetic mechanism, which is most likely regulated by persulfide transfer from SufS to SufE. Taken together, this work provides insight about some key regulatory and mechanistic aspects of SufS that can be extended to other type II cysteine desulfurases and presents questions for further investigations probing the functioning of this complex enzyme system
Porownanie wlasciwosci syntazy tymidylanowej oczyszczonej z tasiemca szczurzego, Hymenolepis diminuta, z wlasciwosciami enzymu zywiciela wyizolowanego z regenerujacej watraby szczura
No full textThymidylate synthases (TS) from the tapeworm, Hymenolepis diminuta, and regenerating rat liver have been purified by means of affinity chromatography on immobilized 10-formyl-5,8-dideazafolate and concentrated on immobilized p-aminophenyl-5-fluoro-2'-deoxyuridine monophosphate. Molecular weights of native TS from the tapeworm and regenerating rat liver were 62 kD and 81.5 kD, respectively, and molecular weights of the monomers were 34.4 kD and 34.9 kD, respectively, painting to dimeric structures of both enzymes. The dependence of TS activity on temperature (ARRHENIUS plot) was biphasic for the parasite enzyme, with lower activation energy above 32°C, and monophasic for the host enzyme. 2'-deoxyuridine-5'-monophosphate (dUMP) analogues, 5-fluoro-2'-deoxyuridine-5' -monophosphate (5-FdUMP), 2-tio-5-FdUMP, N⁴-hydroxy-2'-deoxycytidine-5'-monophosphate (N⁴-hydroxy-dCMP) and N⁴-hydroxy-5-FdCMP, were competitive with respect to dUMP, slow-binding inhibitors of TS from both sources, with K₁ values in 10⁻⁶ - 10⁻⁹ M range. 5-FdUMP was distinctly stronger inhibitor of the host than the tapeworm TS, whereas N⁴-hydroksy-5-FdCMP inhibited stronger the parasite enzyme. Interactions of 5,10-methylenetetrahydrofolate (CH₂H₄PteGlu) analogue, 10-propargyl-5,8-dideazafolate (pddPteGlu), and its di- and triglutamates with both enzymes were studied. Inhibition of the parasite and host enzymes by pddPteGlu was of mixed-type with respect to CH₂H₄PteGlu, with K₁ values in 10⁻⁸ M range. Introduction of additional glutamate residues changed inhibition type to noncompetitive with respect to CH₂H₄PteGlu and lowered K₁ values (pddPteGlu₃ < pddPteGlu₂ < pddPteGlu₁). The latter potentiation of inhibitory properties was distinctly stronger in case of the tapeworm than regenerating rat liver TS
Sexual orientation, minority stress, and attentional bias to threat: A dot-probe and eye tracking study.
No full textResearch has consistently shown that sexual minorities have a disproportionate rate of mental disorders compared to their heterosexual peers, including depression and anxiety (e.g., Wittgens et al., 2022). Minority stress theory (Meyer, 2003) suggests that this is due to social stressors related to their sexual orientation, rather than having a non-heterosexual sexual orientation in itself. Both the psychological mediation framework (Hatzenbuehler, 2009) and rejection sensitivity models (Feinstein, 2020) theorize that cognitive mechanisms link minority stress and poor mental health in sexual minorities. One such understudied mechanism is attentional bias to threat, which is higher in those with depression and anxiety than in those without. Yet, no study to date has examined whether there are sexual orientation-based differences in attentional bias to threat, or whether it is associated with minority stress. Therefore, the current study will examine relationships between sexual orientation, minority stress, and attentional bias to threat using two methods of assessing attentional bias: an emotional dot-probe task and eye tracking.
Feinstein, B. A., Goldfried, M. R., & Davila, J. (2012). The relationship between experiences of discrimination and mental health among lesbians and gay men: An examination of internalized homonegativity and rejection sensitivity as potential mechanisms. Journal of Consulting and Clinical Psychology, 80(5), 917–927. https://doi.org/10.1037/a0029425
Hatzenbuehler, M. L. (2009). How does sexual minority stigma “get under the skin”? A psychological mediation framework. Psychological Bulletin, 135(5), 707–730. https://doi.org/10.1037/a0016441
Meyer, I. H. (2003). Prejudice, social stress, and mental health in lesbian, gay, and bisexual populations: Conceptual issues and research evidence. Psychological Bulletin, 129(5), 674–697. https://doi.org/10.1037/0033-2909.129.5.674
Wittgens, C., Fischer, M. M., Buspavanich, P., Theobald, S., Schweizer, K., & Trautmann, S. (2022). Mental health in people with minority sexual orientations: A meta-analysis of population-based studies. Acta Psychiatrica Scandinavica, 145(4), 357–372. https://doi.org/10.1111/acps.1340
Identification and Inhibition of Fosfomycin Resistance Enzymes for Structure-Based Drug Design
No full textElectronic Thesis or DissertationAntimicrobial resistance (AMR) is a pressing issue facing modern medicine today. Bacteria are developing resistance to antibiotics faster than new antibiotics can be brought to market. Antimicrobial resistant infections are responsible for increased morbidity and mortality rates, as well as an economic burden with increased duration of care and costs of treatments. The development of new antibiotics to combat bacterial resistance is a long and costly process and has resulted in pharmaceutical companies turning away from the traditional drug development pipeline. One alternative method to address AMR is through repurposing existing approved drugs such as by utilizing combination drug therapies. Combination drug therapies often involve the inhibition of antibiotic modifying enzymes found within bacteria. This research aims to use combination therapy to restore the functionality of the drug fosfomycin by using in silico high-throughput virtual screening (HTVS) to identify inhibitors of fosfomycin resistance enzymes.The purpose of this work is to characterize fosfomycin resistance enzymes and identify enzymatic inhibitors to restore the functionality of fosfomycin. First, we identified and characterized the fosfomycin resistance enzyme in Enterococcus faecium (FosBEf). Our goal was to structurally characterize the bacillithiol binding site, however we discovered FosBEf is unique among the FosB enzyme family and utilizes L-cys as the preferred thiol substrate and produced limited enzymatic activity with BSH. Next, we focused on identifying and characterizing inhibitors of the fosfomycin resistance protein in Pseudomonas aeruginosa (FosAPa). Initially we compared the structural and kinetic properties of established inhibitors of other classes of fosfoymcin resistance enzymes on FosA. Then we utilized in silico high-throughput virtual screening (HTVS) to identify halogenated inhibitors to modify the absorption, distribution, metabolism, and excretion properties and potential permeability into P. aeruginosa. Taken together, the findings of this work provide a scaffold for future structure-based drug design for restoring fosfomycin activity
CEERS: Increasing Scatter along the Star-forming Main Sequence Indicates Early Galaxies Form in Bursts
No full textWe present the star formation rate-stellar mass (SFR-M*) relation for galaxies in the Cosmic Evolution Early Release Science survey at 4.5 ≤ z ≤ 12. We model the JWST and Hubble Space Telescope rest-UV and rest-optical photometry of galaxies with flexible star formation histories (SFHs) using BAGPIPES. We consider SFRs averaged from the SFHs over 10 Myr (SFR10) and 100 Myr (SFR100), where the photometry probes SFRs on these timescales, effectively tracing nebular emission lines in the rest-optical (on ~10 Myr timescales) and the UV/optical continuum (on ~100 Myr timescales). We measure the slope, normalization and intrinsic scatter of the SFR-M* relation, taking into account the uncertainty and the covariance of galaxy SFRs and M*. From z ~ 5 to 9 there is larger scatter in the SFR10-M* relation, with σ ( log S F R 100 ) = 0.4 dex, compared to the SFR100-M* relation, with σ ( log S F R 10 ) = 0.1 dex. This scatter increases with redshift and increasing stellar mass, at least out to z ~ 7. These results can be explained if galaxies at higher redshift experience an increase in star formation variability and form primarily in short, active periods, followed by a lull in star formation (i.e., “napping” phases). We see a significant trend in the ratio RSFR = SFR10/SFR100 in which, on average, RSFR decreases with increasing stellar mass and increasing redshift. This yields a star formation “duty cycle” of ~40% for galaxies with log M * / M ⊙ ≥ 9.3 at z ~ 5, declining to ~20% at z ~ 9. Galaxies also experience longer lulls in star formation at higher redshift and at higher stellar mass, such that galaxies transition from periods of higher SFR variability at z ≳ 6 to smoother SFR evolution at z ≲ 4.5
Radon levels in household waters in southern Poland
No full textDetermination of radon concentrations in household waters were performed in 1997 in three regions of south-western Poland which are considered to have an enhanced natural radioactivity level: in the Jelenia Gora and Walbrzych regions (both in south-western Sudety Mountains) and in the Upper Silesian Coal Basin. Water samples were collected from taps, wells and springs and were analyzed in a liquid scintillation counter. In the Upper Silesian Coal Basin all values are below 50 Bq/dm3 with a maximum of 32 Bq/dm3 and in the Sudety Mts. the radon concentration in water exceed this level in 68% of houses, reaching a maximum value of ca. 1400 Bq/dm3 in drilled well water in the Jelenia Gora region. The annual ingestion dose calculated for this value equals to ca. 0.5 mSv for infants, 0.4 mSv for children and 0.3 mSv for adults. The average annual effective whole body doses calculated for tap water samples for a representative population in the investigated regions range from about 0.02 mSv to 0.32 mSv and the maximum value reaches 1.39 mSv. The inhalation doses corresponding to the unit of water-borne radon concentration are about one order higher than the ingestion ones for tap water supplies
The role of AGN and obscuration in the position of the host galaxy relative to the main sequence
No full textInternational audienceWe use X-ray active galactic nuclei (AGN) observed by the Chandra X-ray Observatory within the 9.3 deg2 Boötes field of the NDWFS to study whether there is a correlation between X-ray luminosity (LX) and star formation rate (SFR) of the host galaxy, at 0.5 < z < 2.0, with respect to the position of the galaxy to the main sequence (SFRnorm). About half of the sources in the X-ray sample have spectroscopic redshifts. We also construct a reference galaxy catalogue. For both datasets we use photometric data from the optical to the far-infrared compiled by the HELP project, and apply spectral energy distribution fitting, using the X-CIGALE code. We exclude quiescent sources from both the X-ray and the reference samples. We also account for the mass completeness of our dataset, in different redshifts bins. Our analysis highlights the importance of studying the SFR–LX relation in a uniform manner, taking into account systematics and selection effects. Our results suggest, in less massive galaxies (log [M*(M⊙)] ∼ 11), that an AGN enhances the SFR of the host galaxy by ∼50% compared to non-AGN systems. A flat relation is observed for the most massive galaxies. The SFRnorm does not evolve with redshift. The results, although tentative, are consistent with a scenario where, in less massive systems, both AGN and star formation are fed by cold gas supplied by a merger event. In more massive galaxies the flat relation could be explained by a different supermasssive black hole fuelling mechanism that is decoupled from the star formation of the host galaxy (e.g., hot diffuse gas). Finally, we compare the host galaxy properties of X-ray absorbed and unabsorbed sources. Our results show no difference, which suggests that X-ray absorption is not linked with the properties of the galaxy.Key words: X-rays: general / X-rays: galaxies / galaxies: star formation / quasars: supermassive black holes / galaxies: active⋆ Tables with the X-ray and host galaxy properties used in the analysis are only available at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/cat/J/A+A/653/A7
Comparison of Tetragonal and Ordered Mesoporous Sulfated ZrO<sub>2</sub>: Alkane Isomerization Studied by In Situ DR UV-vis Spectroscopy
No full textIntroduction: The role of the ZrO2 bulk structure in sulfated zirconia (SZ) catalysts is unclear. We compare SZ of tetragonal structure (tSZ) to ordered mesoporous SZ of MCM-41 structure (omSZ), focussing on performance and deactivation behavior in n-butane and n-pentane isomerization. Experimental: tSZ was obtained by calcination of a commercial precursor, omSZ in a procedure based on the description by Ciesla [1,2]. In situ DR-UV-vis-NIR spectra were recorded using a lambda 9 spectrometer (PerkinElmer) with integrating sphere and a fixed bed flow reactor [3]. Products of n-butane (5 kPa in He) and n-pentane (1 kPa) isomerization were analyzed by on-line GC. Results and Discussion: tSZ exhibited a higher maximum activity than omSZ; to obtain comparable rates, conditions were varied. For n-butane isomerization catalyzed by tSZ at 378 K, the conversion increased over 50 min and then declined in the next 100 min to a steady state. Despite a higher reaction temperature of 453 K, omSZ, which passed through a 100 min induction period, deactivated only slowly. Both catalysts produced propane and pentanes as side products, suggesting a similar mode of operation. During the deactivation phase, which stretched over 100 min for tSZ and over more than 900 min for omSZ, bands developed in the UV-vis spectra. A band at 310 nm was detected for tSZ and assigned to allylic cations; for omSZ, the band was positioned at 285 nm. In the reaction with n-pentane, the materials produced more isobutane than isopentane within the observation span of 15 h. Both catalysts deactivated rapidly while bands at 330 nm (tSZ, 298 K) and 285 nm with a shoulder at ca. 330 nm (omSZ, 323 K) formed. Unsaturated species are formed on both materials but they are either differently polarized by the surface or differently structured, indicating an influence of the nature of the ZrO2 structure. 1. U. Ciesla, S. Schacht, G.D. Stucky, K.K. Unger, F. Schüth, Angew. Chem. 108 (1996) 597. 2. X. Yang, F.C. Jentoft, R.E. Jentoft, F. Girgsdies, T. Ressler, Catal. Lett. 81 (2002) 25. 3. M. Thiede, J. Melsheimer, Rev. Sci. Inst. 73 (2002) 394
Comparison of Tetragonal and Ordered Mesoporous Sulfated ZrO2: Alkane Isomerization Studied by In Situ DR UV-vis Spectroscopy
No full textIntroduction: The role of the ZrO2 bulk structure in sulfated zirconia (SZ) catalysts is unclear. We compare SZ of tetragonal structure (tSZ) to ordered mesoporous SZ of MCM-41 structure (omSZ), focussing on performance and deactivation behavior in n-butane and n-pentane isomerization.
Experimental: tSZ was obtained by calcination of a commercial precursor, omSZ in a procedure based on the description by Ciesla [1,2]. In situ DR-UV-vis-NIR spectra were recorded using a lambda 9 spectrometer (PerkinElmer) with integrating sphere and a fixed bed flow reactor [3]. Products of n-butane (5 kPa in He) and n-pentane (1 kPa) isomerization were analyzed by on-line GC.
Results and Discussion: tSZ exhibited a higher maximum activity than omSZ; to obtain comparable rates, conditions were varied. For n-butane isomerization catalyzed by tSZ at 378 K, the conversion increased over 50 min and then declined in the next 100 min to a steady state. Despite a higher reaction temperature of 453 K, omSZ, which passed through a 100 min induction period, deactivated only slowly. Both catalysts produced propane and pentanes as side products, suggesting a similar mode of operation. During the deactivation phase, which stretched over 100 min for tSZ and over more than 900 min for omSZ, bands developed in the UV-vis spectra. A band at 310 nm was detected for tSZ and assigned to allylic cations; for omSZ, the band was positioned at 285 nm. In the reaction with n-pentane, the materials produced more isobutane than isopentane within the observation span of 15 h. Both catalysts deactivated rapidly while bands at 330 nm (tSZ, 298 K) and 285 nm with a shoulder at ca. 330 nm (omSZ, 323 K) formed. Unsaturated species are formed on both materials but they are either differently polarized by the surface or differently structured, indicating an influence of the nature of the ZrO2 structure.
1. U. Ciesla, S. Schacht, G.D. Stucky, K.K. Unger, F. Schüth, Angew. Chem. 108 (1996) 597.
2. X. Yang, F.C. Jentoft, R.E. Jentoft, F. Girgsdies, T. Ressler, Catal. Lett. 81 (2002) 25.
3. M. Thiede, J. Melsheimer, Rev. Sci. Inst. 73 (2002) 394
Search for the Exclusive W Boson Hadronic Decays W± → π±γ, W± → K±γ and W± → ρ±γ with the ATLAS Detector
No full textA search for the exclusive hadronic decays W^{±}→π^{±}γ, W^{±}→K^{±}γ, and W^{±}→ρ^{±}γ is performed using up to 140 fb^{-1} of proton-proton collisions recorded with the ATLAS detector at a center-of-mass energy of sqrt[s]=13 TeV. If observed, these rare processes would provide a unique test bench for the quantum chromodynamics factorization formalism used to calculate cross sections at colliders. Additionally, at future colliders, these decays could offer a new way to measure the W boson mass through fully reconstructed decay products. The search results in the most stringent upper limits to date on the branching fractions B(W^{±}→π^{±}γ)<1.9×10^{-6}, B(W^{±}→K^{±}γ)<1.7×10^{-6}, B(W^{±}→ρ^{±}γ)<5.2×10^{-6} at 95% confidence level
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