Influence of Nanoparticle Size and Shape on Oligomer Formation of an Amyloidogenic Peptide

Understanding the influence of macromolecular crowding and nanoparticles on the formation of in-register $\beta$-sheets, the primary structural component of amyloid fibrils, is a first step towards describing \emph{in vivo} protein aggregation and interactions between synthetic materials and proteins. Using all atom molecular simulations in implicit solvent we illustrate the effects of nanoparticle size, shape, and volume fraction on oligomer formation of an amyloidogenic peptide from the transthyretin protein. Surprisingly, we find that inert spherical crowding particles destabilize in-register $\beta$-sheets formed by dimers while stabilizing $\beta$-sheets comprised of trimers and tetramers. As the radius of the nanoparticle increases crowding effects decrease, implying smaller crowding particles have the largest influence on the earliest amyloid species. We explain these results using a theory based on the depletion effect. Finally, we show that spherocylindrical crowders destabilize the ordered $\beta$-sheet dimer to a greater extent than spherical crowders, which underscores the influence of nanoparticle shape on protein aggregation

A large geometric distortion in the first photointermediate of rhodopsin, determined by double-quantum solid-state NMR

Double-quantum magic-angle-spinning NMR experiments were performed on 11,12-C-13(2)-retinylidene-rhodopsin under illumination at low temperature, in order to characterize torsional angle changes at the C11-C12 photoisomerization site. The sample was illuminated in the NMR rotor at low temperature (similar to 120 K) in order to trap the primary photointermediate, bathorhodopsin. The NMR data are consistent with a strong torsional twist of the HCCH moiety at the isomerization site. Although the HCCH torsional twist was determined to be at least 40A degrees, it was not possible to quantify it more closely. The presence of a strong twist is in agreement with previous Raman observations. The energetic implications of this geometric distortion are discussed

Nutritional strategies of high level natural bodybuilders during competition preparation

Background Competitive bodybuilders employ a combination of resistance training, cardiovascular exercise, calorie reduction, supplementation regimes and peaking strategies in order to lose fat mass and maintain fat free mass. Although recommendations exist for contest preparation, applied research is limited and data on the contest preparation regimes of bodybuilders are restricted to case studies or small cohorts. Moreover, the influence of different nutritional strategies on competitive outcome is unknown. Methods Fifty-one competitors (35 male and 16 female) volunteered to take part in this project. The British Natural Bodybuilding Federation (BNBF) runs an annual national competition for high level bodybuilders; competitors must qualify by winning at a qualifying events or may be invited at the judge’s discretion. Competitors are subject to stringent drug testing and have to undergo a polygraph test. Study of this cohort provides an opportunity to examine the dietary practices of high level natural bodybuilders. We report the results of a cross-sectional study of bodybuilders competing at the BNBF finals. Volunteers completed a 34-item questionnaire assessing diet at three time points. At each time point participants recorded food intake over a 24-h period in grams and/or portions. Competitors were categorised according to contest placing. A “placed” competitor finished in the top 5, and a “Non-placed” (DNP) competitor finished outside the top 5. Nutrient analysis was performed using Nutritics software. Repeated measures ANOVA and effect sizes (Cohen’s d) were used to test if nutrient intake changed over time and if placing was associated with intake. Results Mean preparation time for a competitor was 22 ± 9 weeks. Nutrient intake of bodybuilders reflected a high-protein, high-carbohydrate, low-fat diet. Total carbohydrate, protein and fat intakes decreased over time in both male and female cohorts (P < 0.05). Placed male competitors had a greater carbohydrate intake at the start of contest preparation (5.1 vs 3.7 g/kg BW) than DNP competitors (d = 1.02, 95% CI [0.22, 1.80]). Conclusions Greater carbohydrate intake in the placed competitors could theoretically have contributed towards greater maintenance of muscle mass during competition preparation compared to DNP competitors. These findings require corroboration, but will likely be of interest to bodybuilders and coaches. Keywords BodybuildersCaloriesCompetitionContest preparationDietingEnergy restrictionNaturalNutritionSupplementationPhysiqu

The Mechanism of Substrate Inhibition in Human Indoleamine 2,3-Dioxygenase

Indoleamine 2,3-dioxygenase catalyzes the O(2)-dependent oxidation of L-tryptophan (L-Trp) to N-formylkynurenine (NFK) as part of the kynurenine pathway. Inhibition of enzyme activity at high L-Trp concentrations was first noted more than 30 years ago, but the mechanism of inhibition has not been established. Using a combination of kinetic and reduction potential measurements, we present evidence showing that inhibition of enzyme activity in human indoleamine 2,3-dioxygenase (hIDO) and a number of site-directed variants during turnover with L-tryptophan (L-Trp) can be accounted for by the sequential, ordered binding of O(2) and L-Trp. Analysis of the data shows that at low concentrations of L-Trp, O(2) binds first followed by the binding of L-Trp; at higher concentrations of L-Trp, the order of binding is reversed. In addition, we show that the heme reduction potential (E(m)(0)) has a regulatory role in controlling the overall rate of catalysis (and hence the extent of inhibition) because there is a quantifiable correlation between E(m)(0) (that increases in the presence of L-Trp) and the rate constant for O(2) binding. This means that the initial formation of ferric superoxide (Fe(3+)-O(2)(•-)) from Fe(2+)-O(2) becomes thermodynamically less favorable as substrate binds, and we propose that it is the slowing down of this oxidation step at higher concentrations of substrate that is the origin of the inhibition. In contrast, we show that regeneration of the ferrous enzyme (and formation of NFK) in the final step of the mechanism, which formally requires reduction of the heme, is facilitated by the higher reduction potential in the substrate-bound enzyme and the two constants (k(cat) and E(m)(0)) are shown also to be correlated. Thus, the overall catalytic activity is balanced between the equal and opposite dependencies of the initial and final steps of the mechanism on the heme reduction potential. This tuning of the reduction potential provides a simple mechanism for regulation of the reactivity, which may be used more widely across this family of enzymes

Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment

Small oligomers formed early in the process of amyloid fibril formation may be the major toxic species in Alzheimer's disease. We investigate the early stages of amyloid aggregation for the tau fragment AcPHF6 (Ac-VQIVYK-NH2) using an implicit solvent all-atom model and extensive Monte Carlo simulations of 12, 24, and 36 chains. A variety of small metastable aggregates form and dissolve until an aggregate of a critical size and conformation arises. However, the stable oligomers, which are β-sheet-rich and feature many hydrophobic contacts, are not always growth-ready. The simulations indicate instead that these supercritical oligomers spend a lengthy period in equilibrium in which considerable reorganization takes place accompanied by exchange of chains with the solution. Growth competence of the stable oligomers correlates with the alignment of the strands in the β-sheets. The larger aggregates seen in our simulations are all composed of two twisted β-sheets, packed against each other with hydrophobic side chains at the sheet–sheet interface. These β-sandwiches show similarities with the proposed steric zipper structure for PHF6 fibrils but have a mixed parallel/antiparallel β-strand organization as opposed to the parallel organization found in experiments on fibrils. Interestingly, we find that the fraction of parallel β-sheet structure increases with aggregate size. We speculate that the reorganization of the β-sheets into parallel ones is an important rate-limiting step in the formation of PHF6 fibrils

The Associations of Maternal Health Characteristics, Newborn Metabolite Concentrations, and Child Body Mass Index among US Children in the ECHO Program

We aimed first to assess associations between maternal health characteristics and newborn metabolite concentrations and second to assess associations between metabolites associated with maternal health characteristics and child body mass index (BMI). This study included 3492 infants enrolled in three birth cohorts with linked newborn screening metabolic data. Maternal health characteristics were ascertained from questionnaires, birth certificates, and medical records. Child BMI was ascertained from medical records and study visits. We used multivariate analysis of variance, followed by multivariable linear/proportional odds regression, to determine maternal health characteristic-newborn metabolite associations. Significant associations were found in discovery and replication cohorts of higher pre-pregnancy BMI with increased C0 and higher maternal age at delivery with increased C2 (C0: discovery: aβ 0.05 [95% CI 0.03, 0.07]; replication: aβ 0.04 [95% CI 0.006, 0.06]; C2: discovery: aβ 0.04 [95% CI 0.003, 0.08]; replication: aβ 0.04 [95% CI 0.02, 0.07]). Social Vulnerability Index, insurance, and residence were also associated with metabolite concentrations in a discovery cohort. Associations between metabolites associated with maternal health characteristics and child BMI were modified from 1–3 years (interaction: p < 0.05). These findings may provide insights on potential biologic pathways through which maternal health characteristics may impact fetal metabolic programming and child growth patterns

Measurement of hadronic event shapes in high-p T multijet final states at √s = 13 TeV with the ATLAS detector

A measurement of event-shape variables in proton-proton collisions at large momentum transfer is presented using data collected at s = 13 TeV with the ATLAS detector at the Large Hadron Collider. Six event-shape variables calculated using hadronic jets are studied in inclusive multijet events using data corresponding to an integrated luminosity of 139 fb−1. Measurements are performed in bins of jet multiplicity and in different ranges of the scalar sum of the transverse momenta of the two leading jets, reaching scales beyond 2 TeV. These measurements are compared with predictions from Monte Carlo event generators containing leading-order or next-to-leading order matrix elements matched to parton showers simulated to leading-logarithm accuracy. At low jet multiplicities, shape discrepancies between the measurements and the Monte Carlo predictions are observed. At high jet multiplicities, the shapes are better described but discrepancies in the normalisation are observed. [Figure not available: see fulltext.

Search for pair production of heavy vector-like quarks decaying into high-p T W bosons and top quarks in the lepton-plus-jets final state in pp collisions at √s=13 TeV with the ATLAS detector

A search is presented for the pair production of heavy vector-like B quarks, primarily targeting B quark decays into a W boson and a top quark. The search is based on 36.1 fb−1 of pp collisions at s√=13 TeV recorded in 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. Data are analysed in the lepton-plus-jets final state, characterised by a high-transverse-momentum isolated electron or muon, large missing transverse momentum, and multiple jets, of which at least one is b-tagged. No significant deviation from the Standard Model expectation is observed. The 95% confidence level lower limit on the B mass is 1350 GeV assuming a 100% branching ratio to Wt. In the SU(2) singlet scenario, the lower mass limit is 1170 GeV. The 100% branching ratio limits are found to be also applicable to heavy vector-like X production, with charge +5/3, that decay into Wt. This search is also sensitive to a heavy vector-like B quark decaying into other final states (Zb and Hb) and thus mass limits on B production are set as a function of the decay branching ratio

Alignment of the ATLAS Inner Detector in Run 2

The performance of the ATLAS Inner Detector alignment has been studied using pp collision data at v s = 13 TeV collected by the ATLAS experiment during Run 2 (2015-2018) of the Large Hadron Collider (LHC). The goal of the detector alignment is to determine the detector geometry as accurately as possible and correct for time-dependent movements. The Inner Detector alignment is based on the minimization of track-hit residuals in a sequence of hierarchical levels, from global mechanical assembly structures to local sensors. Subsequent levels have increasing numbers of degrees of freedom; in total there are almost 750,000. The alignment determines detector geometry on both short and long timescales, where short timescales describe movementswithin anLHCfill. The performance and possible track parameter biases originating from systematic detector deformations are evaluated. Momentum biases are studied using resonances decaying to muons or to electrons. The residual sagitta bias and momentum scale bias after alignment are reduced to less than similar to 0.1 TeV-1 and 0.9 x 10(-3), respectively. Impact parameter biases are also evaluated using tracks within jets