Lower polyunsaturated fatty acid levels and FADS2 expression in adult compared to neonatal keratinocytes are associated with FADS2 promotor hypermethylation.

Keratinocytes produce lipids that are critical for the skin barrier, however, little is known about the impact of age on fatty acid (FA) biosynthesis in these cells. We have examined the relationship between keratinocyte FA composition, lipid biosynthetic gene expression, gene promoter methylation and age. Expression of elongase (ELOVL6 and 7) and desaturase (FADS1 and 2) genes was lower in adult versus neonatal keratinocytes, and was associated with lower concentrations of n-7, n-9 and n-10 polyunsaturated FA in adult cells. Consistent with these findings, transient FADS2 knockdown in neonatal keratinocytes mimicked the adult keratinocyte FA profile in neonatal cells. Interrogation of methylation levels across the FADS2 locus (53 genomic sites) revealed differential methylation of 15 sites in neonatal versus adult keratinocytes, of which three hypermethylated sites in adult keratinocytes overlapped with a SMARCA4 protein binding site in the FADS2 promoter.

Simultaneous contrast improvement and temporal compression using divided-pulse nonlinear compression.

We experimentally demonstrate how divided-pulse nonlinear compression can be used to improve the temporal contrast of a laser pulse train while simultaneously temporally compressing the pulses. We measure a contrast improvement of almost four orders of magnitude on a nanosecond time scale and temporally compress the pulses from 1.2 ps to 187 fs. The efficiency of our method is also competitive with other contrast improvement methods, with 72% efficiency measured for the main pulse. We expect the method will be useful in the continuing development of high-power, Yb regenerative amplifiers, which suffer from both significant prepulses and relatively long pulse durations.

Energy scaling beyond the gas ionization threshold with divided-pulse nonlinear compression.

We demonstrate how pulse energy in hollow-core fiber can be scaled beyond gas-ionization limitations using divided-pulse nonlinear compression. With one pulse, ionization limits our fiber's output pulse energy to 2.7 mJ at an input of 4 mJ. By dividing the pulse to four low-energy pulses before the fiber, we eliminated the ionization and scaled the pulse energy 2.5× to 6.6 mJ at an input energy of 10 mJ. Larger energy scaling is possible, as our maximum pulse energy has not reached the new gas ionization threshold. Our results motivate applying the method to state-of-the-art systems for large pulse energy scaling without prohibitive system size increases.

Can biomarkers of extracellular matrix remodelling and wound healing be used to identify high risk patients infected with SARS-CoV-2?: lessons learned from pulmonary fibrosis.

Pulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor's consequent to SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.

Overcoming gas ionization limitations with divided-pulse nonlinear compression.

We simulate Kerr and plasma nonlinearities in a hollow-core fiber to show how plasma effects degrade the output pulse. Our simulations predict the plasma effects can be avoided entirely by implementing divided-pulse nonlinear compression. In divided-pulse nonlinear compression, a high-energy pulse is divided into multiple low-energy pulses, which are spectrally broadened in the hollow-core fiber and then recombined into a high-energy, spectrally broadened pulse. With the plasma effects overcome, spectral broadening can be scaled to larger broadening factors and higher pulse energies. We anticipate this method will also be useful to scale spectral broadening in gas-filled multipass cells.

Critical Issues in Leadership Development for Peer Support Specialists.

This paper is a qualitative analysis of perspectives on leadership development among working peer support specialists and highlights the challenges, needs and efficacy these individuals experience in their work settings. Six participants engaged in a 2 h semi-structured focus group. Participants were guided through a series of nine questions regarding their transition to leadership, professional communication and relationships. Seven themes emerged: managing dual relationships; having difficult conversations; push and pull of leadership; taking responsibility for others; taking responsibility for self-care; addressing stigma in the workplace, and, spirituality/a calling to help. These professionals integrate their personal experiences of recovery into their direct care and leadership approaches in the workplace. This blending of recovery concepts and supervision approaches reflect some of the powerful elements that peer recovery specialists are uniquely qualified to lead in the healthcare workforce. These findings provide important implications for leadership development among this growing segment of the healthcare workforce.

Prediction of effects of dairy selection indexes on methane emissions.

Global warming caused by greenhouse gas emissions is a threat to the survival of humans and other organisms living on Earth. The greenhouse gases released from the dairy sector of New Zealand accounted for 18.2 Mt of carbon dioxide equivalent (CO2-eq) in 2016, mainly from methane generated by enteric fermentation in the rumen of milking cows and their replacement stock. A productivity commission established by the New Zealand government in 2018 estimated that methane emissions from livestock needed to be reduced from 2016 levels by 10 to 22% by 2050 (i.e., 2.8 to 6.1 million t lower), so as to restrict future increases in global temperature to less than 2°C. In this study, we evaluated genetic effects of 8 traits included in the New Zealand national dairy breeding objective, on 3 types of methane emissions metrics: gross methane emissions per dairy cow per year (E), methane emissions per hectare (EH), and methane emissions intensity per milk protein equivalents (EI), as carbon dioxide equivalents. These effects were then aligned with recent genetic changes in these traits brought about by breeding schemes, so that the overall genetic trend for each metric into the future was estimated. The results showed that EH and EI are currently being reduced at rates of -2.31 kg of CO2-eq per hectare per cow per year (current average is 6,915 kg of CO2-eq/ha per cow per year) and -0.04 kg of CO2-eq per kg of milk protein equivalents per cow per year, respectively (current average is 9.7 kg of CO2-eq/milk protein-eq per cow per year). These improvements directly reflect increased production efficiency through selection for farm profitability. If the pastureland area in New Zealand remains the same, at the same productivity and with no increase in supplementation rates from external land sources, in 20 years gross emissions would be reduced by only 0.6%, or 89 Mt. Increased production efficiency will likely result in corresponding changes to the stocking rate, to fully utilize the pasture resource available, and might further encourage a greater rate of intensification via supplementary feeding. Both consequences of current genetic selection could negate any benefits for the national greenhouse gas inventory. New selection criteria for reduced methane production are needed to help achieve New Zealand's national methane reduction targets.

Changes in epidermal morphology associated with dandruff.

OBJECTIVE: Dandruff is a very common scalp condition characterized by flaking and pruritus usually with no visible signs of inflammation, such as redness and erythema. Dandruff is considered a multifactorial condition with both microbial colonization and host factors such as sebum production thought to play a role. There is evidence of changes in epidermal morphology in the scalp skin of dandruff sufferers, with reports of an increase in mean thickness and more nucleated cell layers. The underlying mechanisms driving these morphological changes are currently unclear. The objective of this study was to fully characterize epidermal morphology in dandruff compared to healthy scalp skin and to evaluate potential mechanisms underlying any changes observed. METHODS: Scalp skin biopsies were taken from 22 healthy female subjects and 21 dandruff sufferers, from both lesional and non-lesional sites. Samples were processed, sectioned and stained using haematoxylin and eosin (H&E). To fully characterize epidermal morphology, measurements were taken of epidermal thickness, the convolution of the dermal-epidermal junction and the depth of epidermal rete ridges. To analyse changes in epidermal proliferation immunohistochemical staining was performed using Ki67, a well-established marker of cell proliferation, and quantified using image analysis. RESULTS: Histochemical analysis of skin sections revealed that in dandruff lesional samples, the epidermis was thicker, had a more convoluted dermal epidermal junction and the rete ridges were elongated, compared to healthy scalp skin. Similar directional changes in epidermal morphology, were observed in non-lesional dandruff samples, albeit to a lesser extent. Image analysis of Ki67 expression in the epidermis revealed dandruff lesional skin contained significantly more Ki67-positive proliferating keratinocytes than healthy controls samples. This suggests dandruff scalp skin epidermal keratinocytes are in a hyper-proliferative state. CONCLUSION: There were significant changes in epidermal morphology in dandruff lesional skin compared to healthy scalp skin including increased epidermal thickness, a more convoluted dermal-epidermal junction and elongation of rete ridges. Interestingly, we found there was evidence of an increase in the percentage of epidermal Ki67-positive cells, which has not been reported previously, and demonstrates dandruff is a condition displaying epidermal hyper-proliferation.

OBJECTIF: Les pellicules constituent une affection du cuir chevelu très fréquente caractérisée par une desquamation et un prurit ne présentant pas, en général, des signes visibles d'inflammation, comme une rougeur et un érythème. Les pellicules sont considérées être une affection multifactorielle présentant une colonisation microbienne ainsi que des facteurs-hôtes, tels que la production de sébum, qui pourraient avoir un rôle à jouer. Il existe des preuves qu'il se produit des changements dans la morphologie épidermique de la peau du cuir chevelu des personnes qui ont des pellicules, et des rapports font cas d'une augmentation de l'épaisseur moyenne et d'un plus grand nombre de couches de cellules nucléées. Les mécanismes sous-jacents à ces changements morphologiques sont jusqu'ici peu élucidés. L'objectif de cette étude était de caractériser pleinement la morphologie épidermique en la présence de pellicules par comparaison à la peau du cuir chevelu sain, et d'évaluer les mécanismes potentiels sous-jacents à tout changement observé. MÉTHODES: Des biopsies de la peau du cuir chevelu ont été pratiquées chez 22 femmes en bonne santé et 21 femmes présentant des pellicules, dans des sites lésionnés et non lésionnés. Les échantillons ont été traités, coupés en lamelles et colorés en utilisant de l'hématoxyline et de l'éosine (H&E). Pour caractériser pleinement la morphologie épidermique, des mesures de l'épaisseur épidermique, de la convolution de la jonction dermo-épidermique et de la profondeur des crêtes du réseau épidermique ont été effectuées. Pour analyser les changements dans la prolifération épidermique, une coloration immunohistochimique a été réalisée en utilisant du Ki67, un marqueur bien établi de la prolifération cellulaire, et quantifiée à l'aide de l'analyse d'images. RÉSULTATS: L'analyse histochimique des sections de peau a révélé que, dans les échantillons de lésions avec pellicules, l'épiderme était plus épais, présentait une jonction dermo-épidermique plus compliquée et des crêtes du réseau plus allongées, par comparaison à la peau du cuir chevelu en bonne santé. Des changements directionnels analogues de la morphologie épidermique ont été observés dans les échantillons sans lésions et avec pellicules, toutefois en une moindre mesure. L'analyse des images de l'expression de Ki67 dans l'épiderme a révélé que la peau avec lésions et pellicules contenait des kératinocytes prolifératifs bien plus Ki67-positifs que les échantillons de témoins en bonne santé. Cela suggère que les kératinocytes épidermiques de la peau du cuir chevelu présentant des pellicules sont dans un état hyper-prolifératif. CONCLUSION: Il s'est produit des changements significatifs dans la morphologie épidermique de la peau avec lésions et pellicules, par comparaison à la peau du cuir chevelu en bonne santé, y compris un épaississement de l'épiderme, une jonction dermo-épidermique plus compliquée et un allongement des crêtes du réseau. Fait intéressant, nous avons découvert des signes d'augmentation du pourcentage de cellules épidermiques Ki67-positives, ce qui n'avait encore jamais été rapporté, et qui démontre que la présence de pellicules est une affection affichant une hyper-prolifération épidermique.

Low levels of genetic structuring in King George whiting Sillaginodes punctatus across two geographic regions.

Postlarvae of King George whiting Sillaginodes punctatus, a commercially important fish species in southern Australia, were collected from multiple locations across south and south-eastern Australia. Genetic analyses using seven microsatellite markers found little evidence of genetic structure suggesting high levels of connectivity between the regions. The results found no evidence of a distinct source spawning population within the south-eastern range sampled in this study.

TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics.

Millions of patients suffer from major depressive disorder (MDD), but many do not respond to selective serotonin reuptake inhibitor (SSRI) therapy. We used a pharmacometabolomics-informed pharmacogenomics research strategy to identify genes associated with metabolites that were related to SSRI response. Specifically, 306 MDD patients were treated with citalopram or escitalopram and blood was drawn at baseline, 4 and 8 weeks for blood drug levels, genome-wide single nucleotide polymorphism (SNP) genotyping and metabolomic analyses. SSRI treatment decreased plasma serotonin concentrations (P<0.0001). Baseline and plasma serotonin concentration changes were associated with clinical outcomes (P<0.05). Therefore, baseline and serotonin concentration changes were used as phenotypes for genome-wide association studies (GWAS). GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant (P=7.84E-09) SNP cluster on chromosome four 5' of TSPAN5 and a cluster across ERICH3 on chromosome one (P=9.28E-08) that were also observed during GWAS for change in serotonin at 4 (P=5.6E-08 and P=7.54E-07, respectively) and 8 weeks (P=1.25E-06 and P=3.99E-07, respectively). The SNPs on chromosome four were expression quantitative trait loci for TSPAN5. Knockdown (KD) and overexpression (OE) of TSPAN5 in a neuroblastoma cell line significantly altered the expression of serotonin pathway genes (TPH1, TPH2, DDC and MAOA). Chromosome one SNPs included two ERICH3 nonsynonymous SNPs that resulted in accelerated proteasome-mediated degradation. In addition, ERICH3 and TSPAN5 KD and OE altered media serotonin concentrations. Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may have a role in SSRI treatment outcomes.

Sex-related differential susceptibility to doxorubicin-induced cardiotoxicity in B6C3F1 mice.

Sex is a risk factor for development of cardiotoxicity, induced by the anti-cancer drug, doxorubicin (DOX), in humans. To explore potential mechanisms underlying differential susceptibility to DOX between sexes, 8-week old male and female B6C3F1 mice were dosed with 3mg/kg body weight DOX or an equivalent volume of saline via tail vein once a week for 6, 7, 8, and 9 consecutive weeks, resulting in 18, 21, 24, and 27mg/kg cumulative DOX doses, respectively. At necropsy, one week after each consecutive final dose, the extent of myocardial injury was greater in male mice compared to females as indicated by higher plasma concentrations of cardiac troponin T at all cumulative DOX doses with statistically significant differences between sexes at the 21 and 24mg/kg cumulative doses. A greater susceptibility to DOX in male mice was further confirmed by the presence of cytoplasmic vacuolization in cardiomyocytes, with left atrium being more vulnerable to DOX cardiotoxicity. The number of TUNEL-positive cardiomyocytes was mostly higher in DOX-treated male mice compared to female counterparts, showing a statistically significant sex-related difference only in left atrium at 21mg/kg cumulative dose. DOX-treated male mice also had an increased number of γ-H2A.X-positive (measure of DNA double-strand breaks) cardiomyocytes compared to female counterparts with a significant sex effect in the ventricle at 27mg/kg cumulative dose and right atrium at 21 and 27mg/kg cumulative doses. This newly established mouse model provides a means to identify biomarkers and access potential mechanisms underlying sex-related differences in DOX-induced cardiotoxicity.

Early transcriptional changes in cardiac mitochondria during chronic doxorubicin exposure and mitigation by dexrazoxane in mice.

Identification of early biomarkers of cardiotoxicity could help initiate means to ameliorate the cardiotoxic actions of clinically useful drugs such as doxorubicin (DOX). Since DOX has been shown to target mitochondria, transcriptional levels of mitochondria-related genes were evaluated to identify early candidate biomarkers in hearts of male B6C3F1 mice given a weekly intravenous dose of 3mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8 weeks (6, 9, 12, 18, or 24 mg/kg cumulative DOX doses, respectively). Also, a group of mice was pretreated (intraperitoneally) with the cardio-protectant, dexrazoxane (DXZ; 60 mg/kg) 30 min before each weekly dose of DOX or SAL. At necropsy a week after the last dose, increased plasma concentrations of cardiac troponin T (cTnT) were detected at 18 and 24 mg/kg cumulative DOX doses, whereas myocardial alterations were observed only at the 24 mg/kg dose. Of 1019 genes interrogated, 185, 109, 140, 184, and 451 genes were differentially expressed at 6, 9, 12, 18, and 24 mg/kg cumulative DOX doses, respectively, compared to concurrent SAL-treated controls. Of these, expression of 61 genes associated with energy metabolism and apoptosis was significantly altered before and after occurrence of myocardial injury, suggesting these as early genomics markers of cardiotoxicity. Much of these DOX-induced transcriptional changes were attenuated by pretreatment of mice with DXZ. Also, DXZ treatment significantly reduced plasma cTnT concentration and completely ameliorated cardiac alterations induced by 24 mg/kg cumulative DOX. This information on early transcriptional changes during DOX treatment may be useful in designing cardioprotective strategies targeting mitochondria.

Short communication: Estimates of genetic parameters for dairy fertility in New Zealand.

Reproductive performance of dairy cows in a seasonal calving system is especially important as cows are required to achieve a 365-d calving interval. Prior research with a small data set has identified that the genetic evaluation model for fertility could be enhanced by replacing the binary calving rate trait (CR42), which gives the probability of a cow calving within the first 42d since the planned start of calving at second, third, and fourth calving, with a continuous version, calving season day (CSD), including a heifer calving season day trait expressed at first calving, removing milk yield, retaining a probability of mating trait (PM21) which gives the probability of a cow being mated within the first 21d from the planned start of mating, and first lactation body condition score (BCS), and including gestation length (GL). The aim of this study was to estimate genetic parameters for the proposed new model using a larger data set and compare these with parameters used in the current system. Heritability estimates for CSD and PM21 ranged from 0.013 to 0.019 and from 0.031 to 0.058, respectively. For the 2 traits that correspond with the ones used in the current genetic evaluation system (mating trait, PM21 and BCS) genetic correlations were lower in this study compared with previous estimates. Genetic correlations between CSD and PM21 across different parities were also lower than the correlations between CR42 and PM21 reported previously. The genetic correlation between heifer CSD and CSD in first parity was 0.66. Estimates of genetic correlations of BCS with CSD were higher than those with PM21. For GL, direct heritability was estimated to be 0.67, maternal heritability was 0.11, and maternal repeatability was 0.22. Direct GL had moderate to high and favorable genetic correlations with evaluated fertility traits, whereas corresponding residual correlations remain low, which makes GL a useful candidate predictor trait for fertility in a multiple trait evaluation. The superiority of direct GL genetic component over the maternal GL component for predicting fertility was demonstrated. Future work planned in this area includes the implementation and testing of this new model on national fertility data.

Phenotypic associations between gestation length and production, fertility, survival, and calf traits.

Gestation length may be a useful selection criterion in the genetic evaluation of fertility for New Zealand's predominantly seasonally calving dairy herd. However, it is unknown if calves born following shorter gestation lengths have lower survival or are compromised in their subsequent performance as a milking cow. In this study, data from a large number (~38,000) of cows were first analyzed to determine if those animals born following a short (shortest 5%) or a long (longest 5%) gestation length differed in their subsequent fertility, milk production, and survival compared with intermediate-gestation-length animals. To determine the effect of gestation length on calving difficulty and perinatal mortality, the gestation records of the calves born to these cows (from their heifer and subsequent 6 parities) were also analyzed. Animals born following short gestation lengths had improved fertility (specifically, their probability of being presented for mating in the first 21 d of the mating season was increased by 4 to 5 percentage points and the day of the calving season at which they calved was 2 to 5d earlier), whereas those born following long gestation lengths had decreased fertility (3 to 4% less likely to be presented for mating in the first 21 d of the calving season and calved 3 to 5d later) compared with animals with average gestation lengths. Both short- and long-gestation-length animals produced significantly less milk and solids (e.g., 1.3 to 1.4 kg of protein over a standardized 270-d lactation) relative to intermediate-gestation-length cows, after adjusting for the day of the year they were born. However, for short-gestation-length cows, this effect disappeared when the earlier birth advantage was retained. Short-gestation-length cows did not exhibit a significant reduction in survival compared with intermediate-gestation-length cows. Short gestation length did not affect calving difficulty but long gestation length was negatively associated with this trait (i.e., about 2% higher incidence). Calves gestated for shorter or longer periods were more likely to die in the perinatal period than other calves (3 and 7% higher incidence of mortality, respectively). Overall, the net effects of shortened gestation lengths are likely to be economically positive.

Reflux composition influences the level of NF-κB activation and upstream kinase preference in oesophageal adenocarcinoma cells.

Oesophageal adenocarcinoma (OA) incidence is rising and prognosis is poor. Understanding the molecular basis of this malignancy is key to finding new prevention and treatment strategies. Gastroesophageal reflux disease is the primary cause of OA, usually managed with acid suppression therapy. However, this often does little to control carcinogenic bile acid reflux. The transcription factor nuclear factor kappa B (NF-κB) plays a key role in the pathogenesis of OA and its activity is associated with a poor response to chemotherapy, making it an attractive therapeutic target. We sought to decipher the role of different bile acids in NF-κB activation in oesophageal cell lines using short, physiologically relevant exposure times. The effect of an acidic or neutral extracellular pH was investigated concurrently, to mimic in vivo conditions associated with or without acid suppression. We found that some bile acids activated NF-κB to a greater extent when combined with acid, whereas others did so in its absence, at neutral pH. The precise composition of an individual's reflux, coupled with whether they are taking acid suppressants may therefore dictate the extent of NF-κB activation in the oesophagus, and hence the likelihood of histological progression and chemotherapy success. Regardless of pH, the kinase inhibitor of κB kinase was pivotal in mediating reflux induced NF-κB activation. Its importance was confirmed further as its increased activation was associated with histological progression in patient samples. We identified further kinases important in acid or bile induced NF-κB signalling in oesophageal cells, which may provide suitable targets for therapeutic intervention.

Automation and validation of micronucleus detection in the 3D EpiDerm™ human reconstructed skin assay and correlation with 2D dose responses.

Recent restrictions on the testing of cosmetic ingredients in animals have resulted in the need to test the genotoxic potential of chemicals exclusively in vitro prior to licensing. However, as current in vitro tests produce some misleading positive results, sole reliance on such tests could prevent some chemicals with safe or beneficial exposure levels from being marketed. The 3D human reconstructed skin micronucleus (RSMN) assay is a promising new in vitro approach designed to assess genotoxicity of dermally applied compounds. The assay utilises a highly differentiated in vitro model of the human epidermis. For the first time, we have applied automated micronucleus detection to this assay using MetaSystems Metafer Slide Scanning Platform (Metafer), demonstrating concordance with manual scoring. The RSMN assay's fixation protocol was found to be compatible with the Metafer, providing a considerably shorter alternative to the recommended Metafer protocol. Lowest observed genotoxic effect levels (LOGELs) were observed for mitomycin-C at 4.8 µg/ml and methyl methanesulfonate (MMS) at 1750 µg/ml when applied topically to the skin surface. In-medium dosing with MMS produced a LOGEL of 20 µg/ml, which was very similar to the topical LOGEL when considering the total mass of MMS added. Comparisons between 3D medium and 2D LOGELs resulted in a 7-fold difference in total mass of MMS applied to each system, suggesting a protective function of the 3D microarchitecture. Interestingly, hydrogen peroxide (H2O2), a positive clastogen in 2D systems, tested negative in this assay. A non-genotoxic carcinogen, methyl carbamate, produced negative results, as expected. We also demonstrated expression of the DNA repair protein N-methylpurine-DNA glycosylase in EpiDerm™. Our preliminary validation here demonstrates that the RSMN assay may be a valuable follow-up to the current in vitro test battery, and together with its automation, could contribute to minimising unnecessary in vivo tests by reducing in vitro misleading positives.

Wrinkle reduction in post-menopausal women consuming a novel oral supplement: a double-blind placebo-controlled randomized study.

OBJECTIVE: The maintenance of youthful skin appearance is strongly desired by a large proportion of the world's population. The aim of the present study was therefore to evaluate the effect on skin wrinkling, of a combination of ingredients reported to influence key factors involved in skin ageing, namely inflammation, collagen synthesis and oxidative/UV stress. A supplemented drink was developed containing soy isoflavones, lycopene, vitamin C and vitamin E and given to post-menopausal women with a capsule containing fish oil. METHOD: We have performed a double-blind randomized controlled human clinical study to assess whether this cocktail of dietary ingredients can significantly improve the appearance of facial wrinkles. RESULTS: We have shown that this unique combination of micronutrients can significantly reduce the depth of facial wrinkles and that this improvement is associated with increased deposition of new collagen fibres in the dermis. CONCLUSION: This study demonstrates that consumption of a mixture of soy isoflavones, lycopene, vitamin C, vitamin E and fish oil is able to induce a clinically measureable improvement in the depth of facial wrinkles following long-term use. We have also shown, for the first time with an oral product, that the improvement is associated with increased deposition of new collagen fibres in the dermis.

Pharmacogenomics of selective serotonin reuptake inhibitor treatment for major depressive disorder: genome-wide associations and functional genomics.

A genome-wide association (GWA) study of treatment outcomes (response and remission) of selective serotonin reuptake inhibitors (SSRIs) was conducted using 529 subjects with major depressive disorder. While no SNP associations reached the genome-wide level of significance, 14 SNPs of interest were identified for functional analysis. The rs11144870 SNP in the riboflavin kinase (RFK) gene on chromosome 9 was associated with 8-week treatment response (odds ratio (OR)=0.42, P=1.04 × 10⁻6). The rs915120 SNP in the G protein-coupled receptor kinase 5 (GRK5) gene on chromosome 10 was associated with 8-week remission (OR=0.50, P=1.15 × 10⁻5). Both SNPs were shown to influence transcription by a reporter gene assay and to alter nuclear protein binding using an electrophoretic mobility shift assay. This report represents an example of joining functional genomics with traditional GWA study results derived from a GWA analysis of SSRI treatment outcomes. The goal of this analytical strategy is to provide insights into the potential relevance of biologically plausible observed associations.

Diagnostic correlation between the expression of the DNA repair enzyme N-methylpurine DNA glycosylase and esophageal adenocarcinoma onset: a retrospective pilot study.

EAC in its early stages, when it can potentially be cured, is rarely symptomatic and is associated with high mortality rates because in part of late-stage diagnosis. Given that DNA repair is an important contributory factor of early-stage malignancy, our study focused on the expression of the base excision repair enzyme N-methylpurine DNA glycosylase (MPG) in EAC disease onset. MPG messenger RNA (mRNA) expression levels were determined using quantitative reverse transcriptase polymerase chain reaction from a maximum of 72 patient samples. Immunohistochemistry was further utilized for the detection of MPG protein, and semiquantitative analysis performed using an H-score approach was carried out on a total of 130 archival tissue samples of different esophageal pathologies. Nuclear localized MPG protein was detected in all nonmalignant tissues derived from the enterohepatic system, with H-score values of 3.9-5.5 ± 0.4-1.0. In cancerous tissues derived from the enterohepatic system, a 9.5-fold increase in the level of MPG mRNA expression was specifically observed in the malignant regions located within the esophagus region. Further analysis revealed a 9- and 14-fold increase in MPG mRNA expression in EAC tumor, node, metastasis stages II and III, respectively, suggesting MPG expression to correlate with EAC disease progression. Immunohistochemistry analysis further showed a sevenfold significant increase in MPG protein expression in EAC tissues. Intriguingly, there was a fivefold significant decrease in nuclear localized MPG protein expression in tissues derived from Barrett's esophagus and low-grade dysplasia. Such findings highlight a complex regulatory pattern governing DNA glycosylase base excision repair initiation, as normal tissue undergoes Barrett's metaplasia and later dedifferentiates to EAC. Indeed, disease-stage-specific alterations in the expression of MPG may highlight a potential role for MPG in determining EAC onset and thus potentially be of clinical relevance for early disease detection and increased patient survival.

Carbon nanotube quantum dots as highly sensitive terahertz-cooled spectrometers.

Terahertz technology has recently emerged as a highly sought-after and versatile scientific tool in many fields, including medical imaging, security screening, and wireless communication. However, scientific progress has been hindered by the lack of sources and detectors in this frequency range, thereby known as the terahertz gap. Here, we show that carbon nanotube quantum dots coupled to antennas are extremely sensitive, broad-band, terahertz quantum detectors with spectral resolution. Their response is due to photon-assisted single-electron tunneling and it is substantially enhanced by a novel radiation-induced nonequilibrium cooling of the electrons, causing a sharp height increase of the Coulomb oscillation peaks.