A cross sectional assessment of nutrient intake and the association of the inflammatory properties of nutrients and foods with symptom severity in a large cohort from the UK Multiple Sclerosis Registry.

To assess the intake of nutrients in people with multiple sclerosis (pwMS) compared to a control population, and to assess the pro/ anti-inflammatory properties of nutrients/ foods and their relationships with fatigue and quality of life. This was a cross sectional study in which 2410 pwMS (686 men; 1721 women, 3 n/a, mean age 53 (11 years)) provided dietary data using a food frequency questionnaire that was hosted on the MS Register for a period of 3 months and this was compared to a cohort of 24,852 controls (11,250 male, 13,602 female, mean age 59 years). Consent was implied by anonymously filling out the questionnaire. A Wilcoxon test was used to compare intake between pwMS and controls, and a bivariate analyses followed by chi2 test were undertaken to identify significance and the strength of the relationship between pro/anti-inflammatory dietary factors and fatigue and EQ-5D. Compared to controls, all nutrients were significantly lower in the MS group (P < .05). Bivariate associations showed a significant correlation between consuming fish and lower clinical fatigue (χ2(1) = 4.221, P< .05), with a very low association (φ (phi) = -0.051, P = .04. Positive health outcomes on the EQ-5D measures were associated with higher carotene, magnesium oily fish and fruits and vegetable and sodium consumption (P < .05). Fiber, red meat, and saturated fat (women only) consumption was associated with worse outcomes on the EQ-5D measures (P < .05). pwMS have different dietary intakes compared to controls, and this may be associated with worse symptoms.

The sugar content of children's and lunchbox beverages sold in the UK before and after the soft drink industry levy.

BACKGROUND: Childhood obesity is associated with an increased intake of sugary soft drinks and juice drinks. The aims of this study were (1) to report the sugar and energy content in commercial fruit juice (FJ), juice drinks (JDs) and smoothies (S) specifically targeted at children in the UK, (2) to identify beverages liable for the soft drinks industry levy (SDIL) and (3) to compare the amount of sugar in these beverages before and after the levy. METHODS: The beverages were retrieved using the online shopping tool, my Supermarket, websites of nine major supermarkets in the UK and manufacturers webpages. Comparisons of sugar content were taken before and after the introduction of the SDIL. RESULTS: 131 FJJDS fulfilled the inclusion criteria. The mean sugar content of all the beverages was 6.3 g ± 4.5/100 mL. There was large variation in the sugar content from 0.1 g/100 mL to 15.2 g/100 mL, with smoothies found to contain the most sugar (11.55 ± 1.62 g/mL). The beverages were reanalysed in September 2018 to determine their eligibility for the SDIL. Of the 131 products only seven JDs were eligible for the levy. Four of these beverages had reformulated their ingredients since the initial analysis resulting in a sugar content of <5 g/100 mL. CONCLUSIONS: The majority of the beverages targeted at children and children's lunch boxes were not eligible for the SDIL. This study suggests the necessity to adapt the SDIL to include all FJJDS aimed at children as the total sugar content of these beverages are still above the recommended quantities for this age group.

Distinct transcriptional responses elicited by unfolded nuclear or cytoplasmic protein in mammalian cells.

Eukaryotic cells possess a variety of signaling pathways that prevent accumulation of unfolded and misfolded proteins. Chief among these is the heat shock response (HSR), which is assumed to respond to unfolded proteins in the cytosol and nucleus alike. In this study, we probe this axiom further using engineered proteins called 'destabilizing domains', whose folding state we control with a small molecule. The sudden appearance of unfolded protein in mammalian cells elicits a robust transcriptional response, which is distinct from the HSR and other known pathways that respond to unfolded proteins. The cellular response to unfolded protein is strikingly different in the nucleus and the cytosol, although unfolded protein in either compartment engages the p53 network. This response provides cross-protection during subsequent proteotoxic stress, suggesting that it is a central component of protein quality control networks, and like the HSR, is likely to influence the initiation and progression of human pathologies.

The E3 ubiquitin ligase UBE3C enhances proteasome processivity by ubiquitinating partially proteolyzed substrates.

To maintain protein homeostasis, cells must balance protein synthesis with protein degradation. Accumulation of misfolded or partially degraded proteins can lead to the formation of pathological protein aggregates. Here we report the use of destabilizing domains, proteins whose folding state can be reversibly tuned using a high affinity ligand, as model substrates to interrogate cellular protein quality control mechanisms in mammalian cells using a forward genetic screen. Upon knockdown of UBE3C, an E3 ubiquitin ligase, a reporter protein consisting of a destabilizing domain fused to GFP is degraded more slowly and incompletely by the proteasome. Partial proteolysis is also observed when UBE3C is present but cannot ubiquitinate substrates because its active site has been mutated, it is unable to bind to the proteasome, or the substrate lacks lysine residues. UBE3C knockdown also results in less substrate polyubiquitination. Finally, knockdown renders cells more susceptible to the Hsp90 inhibitor 17-AAG, suggesting that UBE3C protects against the harmful accumulation of protein fragments arising from incompletely degraded proteasome substrates.

Recent progress with FKBP-derived destabilizing domains.

The FKBP-derived destabilizing domains are increasingly being used to confer small molecule-dependent stability to many different proteins. The L106P domain confers instability to yellow fluorescent protein when it is fused to the N-terminus, the C-terminus, or spliced into the middle of yellow fluorescent protein, however multiple copies of L106P do not confer greater instability. These engineered destabilizing domains are not dominant to endogenous degrons that regulate protein stability.

Ribonucleotide reductase inhibitors and future drug design.

Ribonucleotide reductase (RR) is a multisubunit enzyme responsible for the reduction of ribonucleotides to their corresponding deoxyribonucleotides, which are building blocks for DNA replication and repair. The key role of RR in DNA synthesis and cell growth control has made it an important target for anticancer therapy. Increased RR activity has been associated with malignant transformation and tumor cell growth. Efforts for new RR inhibitors have been made in basic and translational research. In recent years, several RR inhibitors, including Triapine, Gemcitabine, and GTI-2040, have entered clinical trial or application. Furthermore, the discovery of p53R2, a p53-inducible form of the small subunit of RR, raises the interest to develop subunit-specific RR inhibitors for cancer treatment. This review compiles recent studies on (1) the structure, function, and regulation of two forms of RR; (2) the role in tumorigenesis of RR and the effect of RR inhibition in cancer treatment; (3) the classification, mechanisms of action, antitumor activity, and clinical trial and application of new RR inhibitors that have been used in clinical cancer chemotherapy or are being evaluated in clinical trials; (4) novel approaches for future RR inhibitor discovery.

A dityrosyl-diiron radical cofactor center is essential for human ribonucleotide reductases.

Ribonucleotide reductase catalyzes the reduction of ribonucleotides to deoxyribonucleotides for DNA biosynthesis. A tyrosine residue in the small subunit of class I ribonucleotide reductase harbors a stable radical, which plays a central role in the catalysis process. We have discovered that an additional tyrosine residue, conserved in human small subunits hRRM2 and p53R2, is required for the radical formation and enzyme activity. Mutations of this newly identified tyrosine residue obliterated the stable radical and the enzymatic activity of human ribonucleotide reductases shown by electron paramagnetic resonance spectroscopy and enzyme activity assays. Three-dimensional structural analysis reveals for the first time that these two tyrosines are located at opposite sides of the diiron cluster. We conclude that both tyrosines are necessary in maintaining the diiron cluster of the enzymes, suggesting that the assembly of a dityrosyl-diiron radical cofactor center in human ribonucleotide reductases is essential for enzyme catalytic activity. These results should provide insights to design better ribonucleotide reductase inhibitors for cancer therapy.