Forever Young: Structural Stability of Telomeric Guanine Quadruplexes in the Presence of Oxidative DNA Lesions*.

Human telomeric DNA, in G-quadruplex (G4) conformation, is characterized by a remarkable structural stability that confers it the capacity to resist to oxidative stress producing one or even clustered 8-oxoguanine (8oxoG) lesions. We present a combined experimental/computational investigation, by using circular dichroism in aqueous solutions, cellular immunofluorescence assays and molecular dynamics simulations, that identifies the crucial role of the stability of G4s to oxidative lesions, related also to their biological role as inhibitors of telomerase, an enzyme overexpressed in most cancers associated to oxidative stress.

Self-reported taste and smell alterations and the liking of oral nutritional supplements with sensory-adapted flavors in cancer patients receiving systemic antitumor treatment.

PURPOSE: Taste and smell alterations (TAs and SAs) are often reported by patients with cancer receiving systemic antitumor therapy and can negatively impact food intake and quality of life. This study aimed to examine the occurrence of TAs and SAs and investigate the impact of TAs on overall liking of oral nutritional supplements (ONS) with warming and cooling sensations. METHODS: Patients receiving systemic antitumor therapy completed a questionnaire on sensory alterations and evaluated overall liking of 5 prototype flavors of Nutridrink® Compact Protein (hot tropical ginger (HTG), hot mango (HM), cool red fruits (CRF), cool lemon (CL), and neutral (N)) on a 10-point scale via a sip test. Differences between patients with and without TAs were investigated using permutation analysis. RESULTS: Fifty patients with various cancer types and treatments were included. Thirty patients (60%) reported TAs and 13 (26%) experienced SAs. Three flavors were rated highly with a liking score > 6 (CRF 6.8 ± 1.7; N 6.5 ± 1.9; HTG 6.0 ± 2.0). Larger variation in ONS liking scores was observed in patients with TAs with or without SAs (4.5-6.9 and 4.6-7.2, respectively) vs. patients without TAs (5.9-6.5). TAs were associated with increased liking of CRF (Δ = + 0.9) and N (Δ = + 1.0) flavors. CONCLUSIONS: TAs and SAs are common in patients with cancer undergoing systemic antitumor therapy. Patients with TAs were more discriminant in liking of ONS flavors compared to patients without TAs, and sensory-adapted flavors appeared to be appreciated. The presence of TAs should be considered when developing or selecting ONS for patients with cancer. TRIAL REGISTRATION: Registration at ClinicalTrials.gov (NCT03525236) on 26 April 2018.

Age group determines the acceptability of protein derived off-flavour.

Many older adults fail to meet their daily protein requirements, potentially due to social, physical and medical factors, including sensory and appetite changes. Additionally, our previous research has identified potential sulfurous off-flavours, originating from heat-treatment of protein ingredients, which could play a role in consumer acceptance. This study aims to determine the hedonic impact of these potential off-flavours when added to a dairy beverage, identify the specific off-flavour concentrations which cause rejection by consumers, and lastly investigate difference in acceptance between older and younger consumers. A rejection threshold (RjT) protocol was used, in combination with Best Estimate Thresholds (BET), whereby sulfurous flavours (dimethyl sulfide, dimethyl disulfide and dimethyl trisulfide), and diacetyl were added to create a range of concentrations. 95 participants (younger n = 49, 18-38 years; older n = 46, 60-79 years) tasted 7 pairs of samples (one blank and one with ascending off-flavour concentration) and selected their preferred samples. Sulfurous flavours negatively impacted consumer acceptance, however, the extent to which they impart a negative effect differs between age groups. Younger adults rejected samples containing low concentrations of sulfurous off-flavours (1.55 ppb), however, older adults rejected samples with concentrations over 3 times higher (5.08 ppb). When combined with sulfurous flavours, diacetyl increased the rejection threshold for both groups. In conclusion, these observations imply that a greater quantity of off-flavour may be present before acceptance is reduced in the older consumer group. Moreover, diacetyl demonstrates partial masking abilities of sulfurous off-flavours, and BET gave a more conservative estimate of acceptability. This knowledge will help guide sensory innovation of high-protein beverages for older consumers to support product acceptance and optimal intake.

Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death.

An intronic expansion of GGGGCC repeats within the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Ataxin-2 with intermediate length of polyglutamine expansions (Ataxin-2 Q30x) is a genetic modifier of the disease. Here, we found that C9ORF72 forms a complex with the WDR41 and SMCR8 proteins to act as a GDP/GTP exchange factor for RAB8a and RAB39b and to thereby control autophagic flux. Depletion of C9orf72 in neurons partly impairs autophagy and leads to accumulation of aggregates of TDP-43 and P62 proteins, which are histopathological hallmarks of ALS-FTD SMCR8 is phosphorylated by TBK1 and depletion of TBK1 can be rescued by phosphomimetic mutants of SMCR8 or by constitutively active RAB39b, suggesting that TBK1, SMCR8, C9ORF72, and RAB39b belong to a common pathway regulating autophagy. While depletion of C9ORF72 only has a partial deleterious effect on neuron survival, it synergizes with Ataxin-2 Q30x toxicity to induce motor neuron dysfunction and neuronal cell death. These results indicate that partial loss of function of C9ORF72 is not deleterious by itself but synergizes with Ataxin-2 toxicity, suggesting a double-hit pathological mechanism in ALS-FTD.

Identification of aroma compounds in a commonly prescribed oral nutritional supplement and associated changes in olfactory abilities with human ageing.

Undernutrition is prevalent in the older adult population. Oral nutritional supplements (ONS) are a clinically effective nutritional intervention, however, patient acceptance of ONS can be limited by their palatability. While sensory attributes such as sweetness and mouthfeel have been investigated, the contribution made by aroma to the perceived flavour of ONS has not been studied. Firstly, this research aimed to identify the aroma active compounds within a commonly prescribed ONS using estimated odour activity values (OAV) and gas chromatography olfactometry mass spectrometry (GC-O-MS). Secondly, age related differences in olfactory detection were explored. Eight aroma active compounds were identified within the ONS, including diacetyl (sweet), isoamyl acetate (banana), dimethyl trisulfide (sulfur) and methanethiol (sulfur). When compared with younger adults (n = 24, 18-44 years), older adults (n = 24, 62-80 years) had higher detection thresholds for all aroma compounds and this was significant for isoamyl acetate (sweet, fruity) and methanethiol (sulfur) (p = 0.01 and p = 0.03, respectively). Thus, a decline in olfactory sensitivity was present in the older subjects included in the study, and this reduced detection sensitivity was aroma specific. Thus, older adults' flavour perception of ONS likely depends on the combined effect of product factors (the aroma profile) along with age related consumer factors (the degree of impairment in perception). This is a fundamental study which will aid future research into how the aroma profile, and associated age related impairments in perception, shape the global perception of ONS for nutritionally at risk older individuals.

C9ORF72 is a GDP/GTP exchange factor for Rab8 and Rab39 and regulates autophagy.

Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS-FTD) are devastating neurodegenerative disease affecting motoneurons from the spinal chord and neurons from the frontal and temporal cortex, respectively. The most common genetic cause for ALS-FTD is an expansion of GGGGCC repeats within the first intron of the C9ORF72 gene. However, little is known on the function of C9ORF72. Recently, other and we found that C9ORF72 forms a stable complex with the SMCR8 and WDR41 proteins. This complex acts as a GDP/GTP exchange factor for the small RAB GTPases Rab8a and Rab39b. Since Rab8 and Rab39 are involved in macroautophagy, we tested the role of C9ORF72 in this mechanism. Decrease expression of C9ORF72 in neuronal cultures leads to autophagy dysfunction characterized by accumulation of aggregates of p62/SQSTM1. However, loss of C9ORF72 expression does not cause major neuronal cell death, suggesting that a second stress may be required to promote cell toxicity. Intermediate size of polyglutamine repeats within Ataxin-2 (ATXN2) is an important genetic modifier of ALS-FTD. We found that decrease expression of C9ORF72 synergizes the toxicity and aggregation of ATXN2 with intermediate size of polyglutamine (30Q). Overall, our data suggest that reduce expression of C9ORF72 causes suboptimal autophagy that sensitizes neurons to a second stress. These data suggest that reduce expression of C9ORF72 may partly contribute to ALS-FTD pathogenesis.