Human serine racemase structure/activity relationship studies provide mechanistic insight and point to position 84 as a hot spot for \u3ci\u3eβ\u3c/i\u3e-elimination function

There is currently great interest in human serine racemase, the enzyme responsible for producing the NMDA co-agonist D-serine. Reported correlation of D-serine levels with disorders including Alzheimer’s disease, ALS, and ischemic brain damage (elevated D-serine) and schizophrenia (reduced D-serine) has further piqued this interest. Reported here is a structure/activity relationship study of position Ser84, the putative re-face base. In the most extreme case of functional reprogramming, the S84D mutant displays a dramatic reversal of β-elimination substrate specificity in favor of L-serine over the normally preferred L-serine-O-sulfate (~1200-fold change in kcat/Km ratios) and L (L-THA; ~5000-fold change in kcat/Km ratios) alternative substrates. On the other hand, the S84T (which performs L-Ser racemization activity), S84A (good kcat but high Km for L-THA elimination), and S84N mutants (nearly WT efficiency for L-Ser elimination) displayed intermediate activity, all showing a preference for the anionic substrates, but generally attenuated compared with the native enzyme. Inhibition studies with L-erythro-β-hydroxyaspartate follow this trend, with both WT serine racemase and the S84N mutant being competitively inhibited, with Ki = 31 ± 1.5 μM and 1.5 ± 0.1mM, respectively, and the S84D being inert to inhibition. Computational modeling pointed to a key role for residue Arg-135 in binding and properly positioning the L-THA and L-serine-O-sulfate substrates and the L-erythro-β-hydroxyaspartate inhibitor. Examination of available sequence data suggests that Arg-135 may have originated for L-THA-like-β-elimination function in earlier evolutionary variants, and examination of available structural data suggests that a Ser84-H2O-Lys114 hydrogen-bonding network in human serine racemase lowers the pKa of the Ser84 re-face base

The Angular Momentum of the Circumgalactic Medium in the TNG100 Simulation

We present an analysis of the angular momentum content of the circumgalactic medium (CGM) using TNG100, one of the flagship runs of the IllustrisTNG project. We focus on Milky Way-mass halos ($\sim 10^{12} \; M_{\odot}$) at $z=0$ but also analyze other masses and redshifts up to $z=5$. We find that the CGM angular momentum properties are strongly correlated with the stellar angular momentum of the corresponding galaxy: the CGM surrounding high-angular momentum galaxies has a systematically higher angular momentum and is better aligned to the rotational axis of the galaxy itself than the CGM surrounding low-angular momentum galaxies. Both the hot and cold phases of the CGM show this dichotomy, though it is stronger for colder gas. The CGM of high-angular momentum galaxies is characterized by a large wedge of cold gas with rotational velocities at least $\sim1/2$ of the halo's virial velocity, extending out to $\sim 1/2$ of the virial radius, and by biconical polar regions dominated by radial velocities suggestive of galactic fountains; both of these features are absent from the CGM of low-angular momentum galaxies. These conclusions are general to halo masses $\lesssim 10^{12} \; M_{\odot}$ and for $z \lesssim 2$, but they do not apply for more massive halos or at the highest redshift studied. By comparing simulations run with alterations to the fiducial feedback model, we identify the better alignment of the CGM to high-angular momentum galaxies as a feedback-independent effect and the galactic winds as a dominant influence on the CGM's angular momentum.Comment: Accepted to ApJ. 16 pages, 12 figure

Tidal Torquing of Elliptical Galaxies in Cluster Environments

Observational studies of galaxy isophotal shapes have shown that galaxy orientations are anisotropic: a galaxy's long axis tends to be oriented toward the center of its host. This radial alignment is seen across a wide range of scales, from galaxies in massive clusters to small Milky Way type satellite systems. Recently, this effect has also been detected in dark matter simulations of cosmological structure, but the degree of alignment of dark matter substructures in these studies is significantly stronger than seen in observations. In this paper we attempt to reconcile these two results by performing high-resolution numerical experiments on N-body multi-component models of triaxial galaxies orbiting in an external analytical potential. The large number of particles employed allows us to probe deep into the inner structure of the galaxy: we show that the discrepancy between observed galaxies and simulated dark matter halos is a natural consequence of induced radial shape twisting in the galaxy by the external potential. The degree of twisting depends strongly on the orbital phase and eccentricity of the satellite, and it can, under certain conditions, be significant at radii smaller than the dark matter scale radius. Such internal misalignments will have important consequences, both for the dynamical evolution of the galaxy itself, and for mass modeling of galaxies in clustered environments.Comment: 19 pages, 22 figures, published in Ap

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Self-Reported Memory Complaints: Implications from a Longitudinal Cohort with Autopsies

OBJECTIVE: We assessed salience of subjective memory complaints (SMCs) by older individuals as a predictor of subsequent cognitive impairment while accounting for risk factors and eventual neuropathologies. METHODS: Subjects (n = 531) enrolled while cognitively intact at the University of Kentucky were asked annually if they perceived changes in memory since their last visit. A multistate model estimated when transition to impairment occurred while adjusting for intervening death. Risk factors affecting the timing and probability of an impairment were identified. The association between SMCs and Alzheimer-type neuropathology was assessed from autopsies (n = 243). RESULTS: SMCs were reported by more than half (55.7%) of the cohort, and were associated with increased risk of impairment (unadjusted odds ratio = 2.8, p \u3c 0.0001). Mild cognitive impairment (dementia) occurred 9.2 (12.1) years after SMC. Multistate modeling showed that SMC reporters with an APOE ε4 allele had double the odds of impairment (adjusted odds ratio = 2.2, p = 0.036). SMC smokers took less time to transition to mild cognitive impairment, while SMC hormone-replaced women took longer to transition directly to dementia. Among participants (n = 176) who died without a diagnosed clinical impairment, SMCs were associated with elevated neuritic amyloid plaques in the neocortex and medial temporal lobe. CONCLUSION: SMC reporters are at a higher risk of future cognitive impairment and have higher levels of Alzheimer-type brain pathology even when impairment does not occur. As potential harbingers of future cognitive decline, physicians should query and monitor SMCs from their older patients

Lamin B1 Depletion in Senescent Cells Triggers Large-Scale Changes in Gene Expression and the Chromatin Landscape

Senescence is a stable proliferation arrest, associated with an altered secretory pathway, thought to promote tumor suppression and tissue aging. While chromatin regulation and lamin B1 down-regulation have been implicated as senescence effectors, functional interactions between them are poorly understood. We compared genome-wide Lys4 trimethylation on histone H3 (H3K4me3) and H3K27me3 distributions between proliferating and senescent human cells and found dramatic differences in senescence, including large-scale domains of H3K4me3- and H3K27me3-enriched “mesas” and H3K27me3-depleted “canyons.” Mesas form at lamin B1-associated domains (LADs) in replicative senescence and oncogene-induced senescence and overlap DNA hypomethylation regions in cancer, suggesting that pre-malignant senescent chromatin changes foreshadow epigenetic cancer changes. Hutchinson-Gilford progeria syndrome fibroblasts (mutant lamin A) also show evidence of H3K4me3 mesas, suggesting a link between premature chromatin changes and accelerated cell senescence. Canyons mostly form between LADs and are enriched in genes and enhancers. H3K27me3 loss is correlated with up-regulation of key senescence genes, indicating a link between global chromatin changes and local gene expression regulation. Lamin B1 reduction in proliferating cells triggers senescence and formation of mesas and canyons. Our data illustrate profound chromatin reorganization during senescence and suggest that lamin B1 down-regulation in senescence is a key trigger of global and local chromatin changes that impact gene expression, aging, and cancer

Isotopic and chemical assessment of the dynamics of methane sources and microbial cycling during early development of an oil sands pit lake

Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).NSERC (CRDPJ 488301-15) and COSIA; FONDECYT, Grant 11191138 (ANID Chile); COPAS COASTAL ANID, FB210021Peer ReviewedWater-capped tailings technology (WCTT) is a key component of the reclamation strategies in the Athabasca oil sands region (AOSR) of northeastern Alberta, Canada. The release of microbial methane from tailings emplaced within oil sands pit lakes, and its subsequent microbial oxidation, could inhibit the development of persistent oxygen concentrations within the water column, which are critical to the success of this reclamation approach. Here, we describe the results of a four-year (2015–2018) chemical and isotopic (δ13C) investigation into the dynamics of microbial methane cycling within Base Mine Lake (BML), the first full-scale pit lake commissioned in the AOSR. Overall, the water-column methane concentrations decreased over the course of the study, though this was dynamic both seasonally and annually. Phospholipid fatty acid (PLFA) distributions and δ13C demonstrated that dissolved methane, primarily input via fluid fine tailings (FFT) porewater advection, was oxidized by the water column microbial community at all sampling times. Modeling and under-ice observations indicated that the dissolution of methane from bubbles during ebullition, or when trapped beneath ice, was also an important source of dissolved methane. The addition of alum to BML in the fall of 2016 impacted the microbial cycling in BML, leading to decreased methane oxidation rates, the short-term dominance of a phototrophic community, and longer-term shifts in the microbial community metabolism. Overall, our results highlight a need to understand the dynamic nature of these microbial communities and the impact of perturbations on the associated biogeochemical cycling within oil sands pit lakes

Customs Law

This article summarizes important developments in 2014 in customs law, including U.S. judicial decisions, trade, legislative, administrative, and executive developments, as well as Canadian and European legal developments