Effects of Dietary Antioxidant Supplementation on Cattle Finished with 30% Wet Distillers Grains Plus Solubles on Fatty Acid Profiles and Display Life

Steers were finished on either 0% wet distillers grains plus solubles or 30% wet distillers grains plus solubles with four antioxidant treatments to evaluate the effects of finishing diets containing wet distillers grains plus solubles, vitamin E and Agrado Plus on beef fatty acid profiles, discoloration and lipid oxidation of retail- displayed beef. Th e inclusion of 30% wet distillers grains plus solubles increased total polyunsaturated fatty acids of beef, but did not promote discoloration or lipid oxidation compared to the 0% wet distillers grains plus solubles diet. In both diets, feeding vitamin E alone or vitamin E+ Agrado Plus was effective in reducing lipid oxidation and maintaining color stability, while supplementing Agrado Plus alone had minimal effects in improving lipid and color stability

The Influence of Diet and Oxidation on Calcium Retention of the Mitochondria in Fresh Beef

Feeding dried distillers grains (DG) may influence calcium flux postmortem by disrupting the stability of the sarcoplasmic reticulum (SR) membrane, thus leading to a higher post- rigor calcium leakage, resulting in greater activation of calpains and improved tenderness. Mitochondria provide the opportunity to study calcium flux in a controlled, tightly defined environment as a model system for the SR. Cattle were finished on diets containing either 0% DG or 50% DG. Feeding DG increased proportions of PUFA in the SR and mitochondrial membrane. Oxidized mitochondria retained less calcium than non- oxidized mitochondria. Mitochondria from cattle finished on corn tended to retain more Ca than mitochondria from cattle finished on DG. These findings suggest that feeding DG in the finishing diet can possibly increase meat tenderness through altered calcium flux

The Influence of Diet and Oxidation on Calcium Retention of the Mitochondria in Fresh Beef

Feeding dried distillers grains (DG) may influence calcium flux postmortem by disrupting the stability of the sarcoplasmic reticulum (SR) membrane, thus leading to a higher post- rigor calcium leakage, resulting in greater activation of calpains and improved tenderness. Mitochondria provide the opportunity to study calcium flux in a controlled, tightly defined environment as a model system for the SR. Cattle were finished on diets containing either 0% DG or 50% DG. Feeding DG increased proportions of PUFA in the SR and mitochondrial membrane. Oxidized mitochondria retained less calcium than non- oxidized mitochondria. Mitochondria from cattle finished on corn tended to retain more Ca than mitochondria from cattle finished on DG. These findings suggest that feeding DG in the finishing diet can possibly increase meat tenderness through altered calcium flux

SETD3 is an actin histidine methyltransferase that prevents primary dystocia.

For more than 50 years, the methylation of mammalian actin at histidine 73 has been known to occur1. Despite the pervasiveness of His73 methylation, which we find is conserved in several model animals and plants, its function remains unclear and the enzyme that generates this modification is unknown. Here we identify SET domain protein 3 (SETD3) as the physiological actin His73 methyltransferase. Structural studies reveal that an extensive network of interactions clamps the actin peptide onto the surface of SETD3 to orient His73 correctly within the catalytic pocket and to facilitate methyl transfer. His73 methylation reduces the nucleotide-exchange rate on actin monomers and modestly accelerates the assembly of actin filaments. Mice that lack SETD3 show complete loss of actin His73 methylation in several tissues, and quantitative proteomics analysis shows that actin His73 methylation is the only detectable physiological substrate of SETD3. SETD3-deficient female mice have severely decreased litter sizes owing to primary maternal dystocia that is refractory to ecbolic induction agents. Furthermore, depletion of SETD3 impairs signal-induced contraction in primary human uterine smooth muscle cells. Together, our results identify a mammalian histidine methyltransferase and uncover a pivotal role for SETD3 and actin His73 methylation in the regulation of smooth muscle contractility. Our data also support the broader hypothesis that protein histidine methylation acts as a common regulatory mechanism

A retroviral link to vertebrate myelination through retrotransposon RNA-mediated control of myelin gene expression

Myelin, the insulating sheath that surrounds neuronal axons, is produced by oligodendrocytes in the central nervous system (CNS). This evolutionary innovation, which first appears in jawed vertebrates, enabled rapid transmission of nerve impulses, more complex brains, and greater morphological diversity. Here, we report that RNA-level expression of RNLTR12-int, a retrotransposon of retroviral origin, is essential for myelination. We show that RNLTR12-int-encoded RNA binds to the transcription factor SOX10 to regulate transcription of myelin basic protein (Mbp, the major constituent of myelin) in rodents. RNLTR12-int-like sequences (which we name RetroMyelin) are found in all jawed vertebrates, and we further demonstrate their function in regulating myelination in two different vertebrate classes (zebrafish and frogs). Our study therefore suggests that retroviral endogenization played a prominent role in the emergence of vertebrate myelin.<br/

Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific SPTLC1 variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in SPTLC2 c.778G>A [p.Glu260Lys] manifesting with juvenile ALS. METHODS: Clinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigation of patients' blood and fibroblasts, was performed. RESULTS: All patients presented with early-childhood-onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration in multiple myotomes, without sensory neuropathy. These findings were supported on ancillary testing including nerve conduction studies and electromyography, muscle biopsies and muscle ultrasound studies. Biochemical investigations in plasma and fibroblasts showed elevated levels of ceramides and unrestrained de novo sphingolipid synthesis. Our studies indicate that SPTLC2 variant [c.778G>A, p.Glu260Lys] acts distinctly from hereditary sensory and autonomic neuropathy (HSAN)-causing SPTLC2 variants by causing excess canonical sphingolipid biosynthesis, similar to the recently reported SPTLC1 ALS associated pathogenic variants. Our studies also indicate that serine supplementation, which is a therapeutic in SPTLC1 and SPTCL2-associated HSAN, is expected to exacerbate the excess sphingolipid synthesis in serine palmitoyltransferase (SPT)-associated ALS. CONCLUSIONS: SPTLC2 is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches

The effect of the apolipoprotein E genotype on response to personalized dietary advice intervention: findings from the Food4Me randomized controlled trial

Background: The apolipoprotein E (APOE) risk allele (ɛ4) is associated with higher total cholesterol (TC), amplified response to saturated fatty acid (SFA) reduction, and increased cardiovascular disease. Although knowledge of gene risk may enhance dietary change, it is unclear whether ɛ4 carriers would benefit from gene-based personalized nutrition (PN). Objectives: The aims of this study were to 1) investigate interactions between APOE genotype and habitual dietary fat intake and modulations of fat intake on metabolic outcomes; 2) determine whether gene-based PN results in greater dietary change than do standard dietary advice (level 0) and nongene-based PN (levels 1–2); and 3) assess the impact of knowledge of APOE risk (risk: E4+, nonrisk: E4−) on dietary change after gene-based PN (level 3). Design: Individuals (n = 1466) recruited into the Food4Me pan-European PN dietary intervention study were randomly assigned to 4 treatment arms and genotyped for APOE (rs429358 and rs7412). Diet and dried blood spot TC and ω-3 (n–3) index were determined at baseline and after a 6-mo intervention. Data were analyzed with the use of adjusted general linear models. Results: Significantly higher TC concentrations were observed in E4+ participants than in E4− (P < 0.05). Although there were no significant differences in APOE response to gene-based PN (E4+ compared with E4−), both groups had a greater reduction in SFA (percentage of total energy) intake than at level 0 (mean ± SD: E4+, −0.72% ± 0.35% compared with −1.95% ± 0.45%, P = 0.035; E4−, −0.31% ± 0.20% compared with −1.68% ± 0.35%, P = 0.029). Gene-based PN was associated with a smaller reduction in SFA intake than in nongene-based PN (level 2) for E4− participants (−1.68% ± 0.35% compared with −2.56% ± 0.27%, P = 0.025). Conclusions: The APOE ɛ4 allele was associated with higher TC. Although gene-based PN targeted to APOE was more effective in reducing SFA intake than standard dietary advice, there was no difference between APOE “risk” and “nonrisk” groups. Furthermore, disclosure of APOE nonrisk may have weakened dietary response to PN

Tuning fresh: radiation through rewiring of central metabolism in streamlined bacteria

Most free-living planktonic cells are streamlined and in spite of their limitations in functional flexibility, their vast populations have radiated into a wide range of aquatic habitats. Here we compared the metabolic potential of subgroups in the Alphaproteobacteria lineage SAR11 adapted to marine and freshwater habitats. Our results suggest that the successful leap from marine to freshwaters in SAR11 was accompanied by a loss of several carbon degradation pathways and a rewiring of the central metabolism. Examples for these are C1 and methylated compounds degradation pathways, the Entner–Doudouroff pathway, the glyoxylate shunt and anapleuretic carbon fixation being absent from the freshwater genomes. Evolutionary reconstructions further suggest that the metabolic modules making up these important freshwater metabolic traits were already present in the gene pool of ancestral marine SAR11 populations. The loss of the glyoxylate shunt had already occurred in the common ancestor of the freshwater subgroup and its closest marine relatives, suggesting that the adaptation to freshwater was a gradual process. Furthermore, our results indicate rapid evolution of TRAP transporters in the freshwater clade involved in the uptake of low molecular weight carboxylic acids. We propose that such gradual tuning of metabolic pathways and transporters toward locally available organic substrates is linked to the formation of subgroups within the SAR11 clade and that this process was critical for the freshwater clade to find and fix an adaptive phenotype.This work was supported by the Swedish Research Council (Grant Numbers 2012-4592 to AE and 2012-3892 to SB) and the Communiy Sequencing Programme of the US Department of Energy Joint Genome Institute. The work conducted by the US Department of Energy Joint Genome Institute, a DOE Office of Science User Facility, is supported under Contract No. DE-AC02-05CH11231