Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage

Environmental and metabolic sources of reactive oxygen species (ROS) can damage DNA, proteins and lipids to promote disease. Regulation of gene expression can prevent this damage and can include increased transcription, translation and post translational modification. Cellular responses to ROS play important roles in disease prevention, with deficiencies linked to cancer, neurodegeneration and ageing. Here we detail basal and damage-induced translational regulation of a group of oxidative-stress response enzymes by the tRNA methyltransferase Alkbh8. Using a new gene targeted knockout mouse cell system, we show that Alkbh8-/- embryonic fibroblasts (MEFs) display elevated ROS levels, increased DNA and lipid damage and hallmarks of cellular stress. We demonstrate that Alkbh8 is induced in response to ROS and is required for the efficient expression of selenocysteine-containing ROS detoxification enzymes belonging to the glutathione peroxidase (Gpx1, Gpx3, Gpx6 and likely Gpx4) and thioredoxin reductase (TrxR1) families. We also show that, in response to oxidative stress, the tRNA modification 5-methoxycarbonylmethyl-2′-O-methyluridi​ne(mcm[superscript 5]Um) increases in normal MEFs to drive the expression of ROS detoxification enzymes, with this damage-induced reprogramming of tRNA and stop-codon recoding corrupted in Alkbh8[superscript -/-] MEFS. These studies define Alkbh8 and tRNA modifications as central regulators of cellular oxidative stress responses in mammalian systems. In addition they highlight a new animal model for use in environmental and cancer studies and link translational regulation to the prevention of DNA and lipid damage.National Institute of Environmental Health Sciences (ES002109)National Institute of Environmental Health Sciences (ES015037)National Institute of Environmental Health Sciences (ES017010)Westaway Research FundDavid H. Koch Institute for Integrative Cancer Research at MIT (Cancer Research Graduate Fellowship)Howard Hughes Medical Institute (Graduate Fellowship)Singapore-MIT Alliance for Research and Technolog

Preparing Students for Team-Based Care for Vulnerable Populations

Health professionals have an obligation to improve both the health of the individual and the public in a time of scarce resources. The Institute of Medicine (IOM), Healthy People Curriculum Task Force and professional education accreditation standards indicate the need for health care professionals to demonstrate competencies related to community engagement, basic health promotion skills and the ability to work effectively in interprofessional teams. An Interprofessional Course, IPE 413: Developing Care for a Vulnerable Population provides students the opportunity to collaborate to address health needs in cooperation with a community partner. Students work in teams to address the complex health care needs of an individual community member. The one hour elective course is open to students from nursing, occupational therapy, pharmacy, social work, and exercise science. Efforts are underway to explore the possibility of offering this course to medical students. Students are assessed on the knowledge and experience gained through this interprofessional experience using the Team Skills Scale and student reflections. Faculties from each of the disciplines utilize a collaborative model in the instructional design of the course. The content is co-taught and faculty not only role model interprofessional care, but also serve as mentors and resource personnel for the students as they work with their clients

Ageless Aluminum-Cerium-Based Alloys in High-Volume Die Casting for Improved Energy Efficiency

Strong chemical reactions between Al and Ce lead to the formation of intermetallics with exceptional thermal stability. The rapid formation of intermetallics directly from the liquid phase during solidification of Al-Ce alloys leads to an ultrafine microconstituent structure that effectively strengthens as-cast alloys without further microstructural optimization via thermal processing. Die casting is a high-volume manufacturing technology that accounts for greater than 40% of all cast Al products, whereas Ce is highly overproduced as a waste product of other rare earth element (REE) mining. Reducing heat treatments would stimulate significant improvements in manufacturing energy efficiency, exceeding (megatonnes/year) per large-scale heat-treatment line. In this study, multiple compositions were evaluated with wedge mold castings to test the sensitivity of alloys to the variable solidification rate inherent in high-pressure die casting. Once a suitable composition was determined, it was successfully demonstrated at 800 lbs/h in a 600-ton die caster, after which the as-die cast parts performed similarly to ubiquitous A380 in the same geometry without requiring heat treatment. This work demonstrates the compatibility of Al REE alloys with high-volume die-casting applications with minimal heat treatments

A massive quiescent galaxy at redshift 4.658

A. C. Carnall thanks the Leverhulme Trust for their support via a Leverhulme Early Career Fellowship. R. J. McLure, J. S. Dunlop, D. J. McLeod, V. Wild, R. Begley, C. T. Donnan and M. L. Hamadouche acknowledge the support of the Science and Technology Facilities Council. F. Cullen acknowledges support from a UKRI Frontier Research Guarantee Grant (grant reference EP/X021025/1). A. Cimatti acknowledges support from the grant PRIN MIUR 2017 - 20173ML3WW 001.The extremely rapid assembly of the earliest galaxies during the first billion years of cosmic history is a major challenge for our understanding of galaxy formation physics (1; 2; 3; 4; 5). The advent of JWST has exacerbated this issue by confirming the existence of galaxies in significant numbers as early as the first few hundred million years (6; 7; 8). Perhaps even more surprisingly, in some galaxies, this initial highly efficient star formation rapidly shuts down, or quenches, giving rise to massive quiescent galaxies as little as 1.5 billion years after the Big Bang (9; 10), however, due to their faintness and red colour, it has proven extremely challenging to learn about these extreme quiescent galaxies, or to confirm whether any exist at earlier times. Here we report the spectroscopic confirmation of a massive quiescent galaxy, GS-9209, at redshift, z = 4.658, just 1.25 billion years after the Big Bang, using JWST NIRSpec. From these data we infer a stellar mass of M∗ = 3.8 ± 0.2 × 1010 M⊙, which formed over a ≃ 200 Myr period before this galaxy quenched its star formation activity at z=6.5+0.2−0.5, when the Universe was ≃ 800 million years old. This galaxy is both a likely descendent of the highest-redshift submillimetre galaxies and quasars, and a likely progenitor for the dense, ancient cores of the most massive local galaxies.PostprintPeer reviewe

Loss of capillary pericytes and the blood–brain barrier in white matter in poststroke and vascular dementias and Alzheimer’s disease

White matter (WM) disease is associated with disruption of the gliovascular unit, which involves breach of the blood‐brain barrier (BBB). We quantified pericytes as components of the gliovascular unit and assessed their status in vascular and other common dementias. Immunohistochemical and immunofluorescent methods were developed to assess the distribution and quantification of pericytes connected to the frontal lobe WM capillaries. Pericytes with a nucleus were identified by collagen 4 (COL4) and platelet derived growth factor receptor‐β (PDGFR‐β) antibodies with further verification using PDGFR‐β specific ELISA. We evaluated a total of 124 post‐mortem brains from subjects with post‐stroke dementia (PSD), vascular dementia (VaD), Alzheimer’s disease (AD), AD‐VaD (Mixed), and post‐stroke non‐demented (PSND) stroke survivors as well as normal ageing controls. COL4 and PDGFR‐β reactive pericytes adopted the characteristic “crescent” or nodule‐like shapes around capillary walls. We estimated densities of pericyte somata to be 225 ±38 and 200 ±13 (SEM) per COL4 mm2 area or 2.0 ±0.1 and 1.7 ±0.1 per mm capillary length in young and older ageing controls. Remarkably, WM pericytes were reduced by ~35‐45 percent in the frontal lobe of PSD, VaD, Mixed and AD subjects compared to PSND and controls subjects (P<0.001). We also found pericyte numbers were correlated with PDGFR‐β reactivity in the WM. Our results first demonstrate a reliable method to quantify COL4‐positive pericytes and then indicate that deep WM pericytes are decreased across different dementias including PSD, VaD, Mixed and AD. Our findings suggest that down regulation of pericytes is associated with the disruption of the BBB in the deep WM in several ageing‐related dementias

The stellar metallicities of massive quiescent galaxies at 1.0 < z < 1.3 from KMOS+VANDELS

We present a rest-frame UV-optical stacked spectrum representative of massive quiescent galaxies at $1.010.8$. The stack is constructed using VANDELS survey data, combined with new KMOS observations. We apply two independent full-spectral-fitting approaches, measuring a total metallicity, [Z/H]=$-0.13\pm0.08$ with Bagpipes, and [Z/H]=$0.04\pm0.14$ with Alf, a fall of $\sim0.2-0.3$ dex compared with the local Universe. We also measure an iron abundance, [Fe/H] =$-0.18\pm0.08$, a fall of $\sim0.15$ dex compared with the the local Universe. We measure the alpha enhancement via the magnesium abundance, obtaining [Mg/Fe]=$0.23\pm$0.12, consistent with similar-mass galaxies in the local Universe, indicating no evolution in the average alpha enhancement of log$(M_*/\rm{M_\odot})=11$ quiescent galaxies over the last $\sim8$ Gyr. This suggests the very high alpha enhancements recently reported for several bright $z\sim1-2$ quiescent galaxies are due to their extreme masses, log$(M_*/\rm{M_\odot})\gtrsim11.5$, rather than being typical of the $z\gtrsim1$ population. The metallicity evolution we observe with redshift (falling [Z/H], [Fe/H], constant [Mg/Fe]) is consistent with recent studies. We recover a mean stellar age of $2.5^{+0.6}_{-0.4}$ Gyr, corresponding to a formation redshift, z_\rm{form}=2.4^{+0.6}_{-0.3}. Recent studies have obtained varying average formation redshifts for $z\gtrsim1$ massive quiescent galaxies, and, as these studies report consistent metallicities, we identify different star-formation-history models as the most likely cause. Larger spectroscopic samples from upcoming ground-based instruments will provide precise constraints on ages and metallicities at $z\gtrsim1$. Combining these with precise JWST $z>2$ quiescent-galaxy stellar-mass functions will provide an independent test of formation redshifts derived from spectral fitting.Comment: 16 pages, 3 figures, accepted for publication in Ap

Hypocholesterolemic and prebiotic effects of a whole-grain oat-based granola breakfast cereal in a cardio-metabolic "At Risk" population

Meta-analyses of randomized controlled trials (RTC) have confirmed the hypocholesterolaemic effect of oats and oat based fibers. However, the mechanisms by which oats or oat fractions lower cholesterol is not totally clear. Recognizing the important role of the gut microbiome in metabolism and metabolic disease risk, we examined the impact of whole grain oat Granola (WGO) on the human gut microbiota and cardio-metabolic risk factors using a randomized crossover dietary intervention in at risk individuals (ClinicalTrials.gov Identifier: NCT01925365). We randomized 32 individuals at risk of developing cardio-metabolic disease by virtue of mild hypercholesterolaemia or glucose intolerance, into two groups consuming either 45 g of WGO or non-whole grain (NWG) breakfast cereals daily for two 6-week intervention periods separated by a 4-week wash out period in a randomized, controlled, crossover, double-blinded design. Confirming the cholesterol lowering effect of WGO, we observed a significant time by treatment interaction, for total cholesterol (TC) (P = 0.0001) and LDL-cholesterol (LDL-C) (P = 0.02) compared to NWG. A significant time by treatment interaction was also observed for the relative abundance of fecal bifidobacteria (P = 0.0001), lactobacilli (P = 0.001) and total bacterial count (P = 0.008), which were all elevated after consumption of WGO. Daily consumption of WGO resulted in a prebiotic effect on the human gut microbiota composition and significant reductions in TC and LDL-C concentrations. Prebiotic modulation of the human gut microbiota may thus constitute a previously unrecognized mechanism contributing to the hypocholesterolaemic effects of whole grain oat Granola

Structural basis for LMO2-driven recruitment of the SCL: E47bHLH heterodimer to hematopoietic-specific transcriptional targets

Cell fate is governed by combinatorial actions of transcriptional regulators assembling into multiprotein complexes. However, the molecular details of how these complexes form are poorly understood. One such complex, which contains the basic-helix-loop-helix heterodimer SCL:E47 and bridging proteins LMO2:LDB1, critically regulates hematopoiesis and induces Tcell leukemia. Here, we report the crystal structure of (SCL:E47)bHLH:LMO2:LDB1LID bound to DNA, providing a molecular account of the network of interactions assembling this complex. This reveals an unexpected role for LMO2. Upon binding to SCL, LMO2 induces new hydrogen bonds in SCL:E47, thereby strengthening heterodimer formation. This imposes a rotation movement onto E47 that weakens the heterodimer:DNA interaction, shifting the main DNA-binding activity onto additional protein partners. Along with biochemical analyses, this illustrates, at an atomic level, how hematopoietic-specific SCL sequesters ubiquitous E47 and associated cofactors and supports SCL'sreported DNA-binding-independent functions. Importantly, this work will drive the design of small molecules inhibiting leukemogenic processes. © 2013 The Authors