Synthesis of 6,8-diaminopurines via acid-induced cascade cyclization of 5-aminoimidazole precursors and preliminary anticancer evaluation.

Inspired by the pharmacological interest generated by 6-substituted purine roscovitine for cancer treatment, 5-aminoimidazole-4-carboxamidine precursors containing a cyanamide unit were prepared by condensation of 5-amino-N-cyanoimidazole-4-carbimidoyl cyanides with a wide range of primary amines. When these amidine precursors were combined with acids, a fast cascade cyclization occurred at room temperature, affording new 6,8-diaminopurines with the N-3 and N-6 substituents changed relatively to the original positions they occupied in the amidine and imidazole moieties of precursors. The efficacy and wide scope of this method was well demonstrated by an easy and affordable synthesis of 22 6,8-diaminopurines decorated with a wide diversity of substituents at the N-3 and N-6 positions of the purine ring. Preliminary in silico and in vitro assessments of these 22 compounds were carried out and the results showed that 13 of these tested compounds not only exhibited IC50 values between 1.4 and 7.5 µM against the colorectal cancer cell line HCT116 but also showed better binding energies than known inhibitors in docking studies with different cancer-related target proteins. In addition, good harmonization observed between in silico and in vitro results strengthens and validates this preliminary evaluation, suggesting that these novel entities are good candidates for further studies as new anticancer agents.

Deep Pressure Therapy: A Promising Anxiety Treatment for Individuals With High Touch Comfort?

One method for managing anxiety, a highly prevalent modern mental health condition, is the calming touch sensations of deep pressure therapy (DPT). Solutions for administering DPT include the Automatic Inflatable DPT (AID) Vest, which we designed in past work. Although benefits of DPT are clear in a subset of the related literature, these benefits are not ubiquitous. There is limited understanding of what factors lead to DPT success for a given user. In this work, we present the findings of a user study ( N = 25) that evaluates the effects of the AID Vest on anxiety. We compared physiological and self-reported measures of anxiety across Active (inflating) and Control (inactive) states of the AID Vest. In addition, we considered the presence of placebo effects and assessed participant comfort with social touch as a potential moderator. The results support our ability to reliably induce anxiety, and show that the Active AID Vest tended to reduce biosignals related to anxiety. We also found a significant relationship between comfort with social touch and reductions in self-reported state anxiety for the Active condition. Those who seek to successfully deploy DPT can benefit from this work.

Ursolic Acid Impairs Cellular Lipid Homeostasis and Lysosomal Membrane Integrity in Breast Carcinoma Cells.

Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies is of utmost importance. Ursolic acid is a naturally occurring pentacyclic triterpene with a wide range of pharmacological activities including anti-inflammatory and anti-neoplastic effects. The latter has been assigned to its ability to promote apoptosis and inhibit cancer cell proliferation by poorly defined mechanisms. In this report, we identify lysosomes as the essential targets of the anti-cancer activity of ursolic acid. The treatment of MCF7 breast cancer cells with ursolic acid elevates lysosomal pH, alters the cellular lipid profile, and causes lysosomal membrane permeabilization and leakage of lysosomal enzymes into the cytosol. Lysosomal membrane permeabilization precedes the essential hallmarks of apoptosis placing it as an initial event in the cascade of effects induced by ursolic acid. The disruption of the lysosomal function impairs the autophagic pathway and likely partakes in the mechanism by which ursolic acid kills cancer cells. Furthermore, we find that combining treatment with ursolic acid and cationic amphiphilic drugs can significantly enhance the degree of lysosomal membrane permeabilization and cell death in breast cancer cells.

Can dietary flavonoids be useful in the personalized treatment of colorectal cancer?

Activating mutations in the oncogenes KRAS, BRAF and PI3K define molecular colorectal cancer (CRC) subtypes because they play key roles in promoting CRC development and in determining the efficacy of chemotherapeutic agents such as 5-fluorouracil and anti-epidermal growth factor receptor monoclonal antibodies. Survival of patients with cancers displaying these molecular profiles is low. Given the limited efficacy of therapeutic strategies for CRC presenting mutational activations in mitogen-activated protein kinase and/or PI3K pathways, developing combination therapies with natural flavonoids or other phytochemicals with demonstrated effects on these pathways (and little or no toxic effects) may constitute a valuable path forward. Much has been published on the anticancer effects of dietary phytochemicals. However, even an exhaustive characterization of potential beneficial effects produced by in vitro studies cannot be extrapolated to effects in humans. So far, the available data constitute a good starting point. Published results show quercetin and curcumin as possibly the best candidates to be further explored in the context of adjuvant CRC therapy either as part of dietary prescriptions or as purified compounds in combination regimens with the drugs currently used in CRC treatment. Clinical trial data is still largely missing and is urgently needed to verify relevant effects and for the development of more personalized treatment approaches.

Sambucus nigra flower and berry extracts for food and therapeutic applications: effect of gastrointestinal digestion on in vitro and in vivo bioactivity and toxicity.

The bioavailability of natural compounds should be assessed through different perspectives. Studying the behaviour of the extracts after digestion is often overlooked but is crucial for success in the development of active food ingredients. Thus, the bioaccessibility of S. nigra (flower and berry) extracts after in vitro gastrointestinal digestion and their effect on toxicity and bioactive potential were studied. The flower extract had a higher content of phenolic compounds, like rutin, chlorogenic acid and rosmarinic acid, while in the berry extract, rutin, resveratrol, ferulic acid and chlorogenic acid were the main phenolic compounds. The effect of the non-digested and digested extracts was significantly different on different cell lines. The IC50 of the normal cell line (L929) was the highest, indicating low toxicity. The IC50 of the cancerous cell lines (HeLa and HT29) was lower, particularly the extract obtained from the flower upon digestion. In the presence of an oxidant agent - tbHP, only the berry extract was able to significantly reduce the formation of ROS in the L929 cell line, while in the HeLa cells, all the extracts were able to reduce ROS formation. The in vivo Artemia salina lethality bioassay demonstrated a dose-dependent effect of extracts, and the berry digested extract induced the lowest mortality rate. The promising results obtained on the chemical and biological evaluation of the extracts indicate that the natural compounds isolated from S. nigra by-products can be used as potential ingredients for functional food formulations and/or as bio-therapeutic agents.

Explicit Instruction of Scientific Uncertainty in an Undergraduate Geoscience Field-Based Course.

Understanding and communicating uncertainty is a key skill needed in the practice of science. However, there has been little research on the instruction of uncertainty in undergraduate science education. Our team designed a module within an online geoscience field course which focused on explicit instruction around uncertainty and provided students with an uncertainty rating scale to record and communicate their uncertainty with a common language. Students then explored a complex, real-world geological problem about which expert scientists had previously made competing claims through geologic maps. Provided with data, expert uncertainty ratings, and the previous claims, students made new geologic maps of their own and presented arguments about their claims in written form. We analyzed these reports along with assessments of uncertainty. Most students explicitly requested geologists' uncertainty judgments in a post-course assessment when asked why scientists might differ in their conclusions and/or utilized the rating scale unprompted in their written arguments. Through the examination of both pre- and post-course assessments of uncertainty and students' course-based assessments, we argue that explicit instruction around uncertainty can be introduced during undergraduate coursework and could facilitate geoscience novices developing into practicing geoscientists.

Chemical Characterization of Sambucus nigra L. Flowers Aqueous Extract and Its Biological Implications.

The main goal of this study was to chemically characterize an aqueous S. nigra flower extract and validate it as a bioactive agent. The elderflower aqueous extraction was performed at different temperatures (50, 70 and 90 °C). The extract obtained at 90 °C exhibited the highest phenolic content and antiradical activity. Therefore, this extract was analyzed by GC-MS and HPLC-MS, which allowed the identification of 46 compounds, being quercetin and chlorogenic acid derivatives representative of 86% of the total of phenolic compounds identified in hydrophilic fraction of the aqueous extract. Naringenin (27.2%) was the major compound present in the lipophilic fraction. The antiproliferative effects of the S. nigra extract were evaluated using the colon cancer cell lines RKO, HCT-116, Caco-2 and the extract's antigenotoxic potential was evaluated by the Comet assay in RKO cells. The RKO cells were the most susceptible to S. nigra flower extract (IC50 = 1250 µg mL-1). Moreover, the extract showed antimicrobial activity against Gram-positive bacteria, particularly Staphylococcus aureus and S. epidermidis. These results show that S. nigra-based extracts can be an important dietary source of bioactive phenolic compounds that contribute to health-span improving life quality, demonstrating their potential as nutraceutical, functional foods and/or cosmetic components for therapeutic purposes.

Spatially and temporally distributed data foraging decisions in disciplinary field science.

How do scientists generate and weight candidate queries for hypothesis testing, and how does learning from observations or experimental data impact query selection? Field sciences offer a compelling context to ask these questions because query selection and adaptation involves consideration of the spatiotemporal arrangement of data, and therefore closely parallels classic search and foraging behavior. Here we conduct a novel simulated data foraging study-and a complementary real-world case study-to determine how spatiotemporal data collection decisions are made in field sciences, and how search is adapted in response to in-situ data. Expert geoscientists evaluated a hypothesis by collecting environmental data using a mobile robot. At any point, participants were able to stop the robot and change their search strategy or make a conclusion about the hypothesis. We identified spatiotemporal reasoning heuristics, to which scientists strongly anchored, displaying limited adaptation to new data. We analyzed two key decision factors: variable-space coverage, and fitting error to the hypothesis. We found that, despite varied search strategies, the majority of scientists made a conclusion as the fitting error converged. Scientists who made premature conclusions, due to insufficient variable-space coverage or before the fitting error stabilized, were more prone to incorrect conclusions. We found that novice undergraduates used the same heuristics as expert geoscientists in a simplified version of the scenario. We believe the findings from this study could be used to improve field science training in data foraging, and aid in the development of technologies to support data collection decisions.

Ohmic Heating Extract of Vine Pruning Residue Has Anti-Colorectal Cancer Activity and Increases Sensitivity to the Chemotherapeutic Drug 5-FU.

Vine pruning residues are by-products of the wine industry that have not received much attention in the past, in spite of being rich in bioactive compounds. In this study, we aimed to test whether an ohmic extract of vine pruning residue (VPE) has anti-colorectal cancer (CRC) properties, and whether responses differ according with cell's mutation profile. VPE decreased human CRC cell proliferation, accompanied by DNA effects and cell cycle modulation. VPE also increased cell sensitivity to the chemotherapeutic drug 5-FU. Our results suggest that tumors harboring BRAF mutations may be more responsive to VPE than KRAS mutated tumors. These effects of the extract were not completely reproduced by the most abundant constituents tested individually at the concentrations present in the effective dose of VPE. Globally, our results indicate that VPE, a polyphenol enriched extract produced by ohmic heating of vine pruning residue, has anti-colorectal cancer potential, including sensitizing to a chemotherapeutical drug, and its use in functional foods or nutraceuticals could be exploited in personalized anti colorectal cancer dietary strategies. Valorization of this lignocellulosic residue should encourage bio-waste recycling, adding value to this agricultural by-product and promoting the sustainable use of natural resources.

In Vitro Modulation of Gut Microbiota and Metabolism by Cooked Cowpea and Black Bean.

Legumes are a rich source of a wide range of compounds that may represent an important tool to overcome gut dysbiosis. In this work, the prebiotic potential of two cooked legumes (cowpea and black bean) was investigated in comparison with potato:beef mixture, as substrates in batch faecal culture fermentation. Prior to the fermentation, all the samples were in vitro digested, passing through three phases, namely mouth, gastric and small intestine simulation, and then in vitro fermented for 6, 24 and 48 h. The shift of pH, production of gas and short-chain fatty acids (SCFAs) and changes in gut microbiota were evaluated along the fermentation time. The pH decreased significantly over time in all media with fermentable sources when compared with the negative control. Gas production was higher in the media containing fermentable source than in the negative control and decreased with fermentation time. The concentration of SCFAs increased over time and it was significantly higher for both legumes than in inulin (positive control) and potato:beef meal. Acetate was the major SCFAs produced during fermentation, particularly in media containing legumes. Both legumes presented a strong prebiotic effect on gut microbiota, showing a significant increase in Bifidobacterium and Lactobacillus. These results suggest that consumption of cooked cowpea and black bean, used alone or as an ingredient of novel functional foods, may contribute to improving intestinal health and therefore human health promotion.

Ohmic heating polyphenolic extracts from vine pruning residue with enhanced biological activity.

Vine Pruning residue was submitted to conventional heating and ohmic heating (OH) for the extraction of bioactive compounds and analyzed for total phenolic content (TPC), polyphenolic profile, antioxidant activity, antimicrobial activity and anticancer activity. The OH extracts were obtained using Low electric field (496.0 V/cm) or Intermediate electric field - IEF (840.0 V/cm). The tests were performed using 45% (v/v) ethanol-water extraction solution at 80 °C at different extraction times (20-90 min). The extract that stood out among the others concerning anticancer potential was the one obtained by OH when used, IEF, where the TPC was significantly higher than in the other extracts which correlated with higher antioxidant, antimicrobial and anti-proliferative activity on different tumor cell lines (HepG2, MDA-MB-231, MCF-7 and Caco2). Vine pruning OH extracts obtained using green solvents by an eco-friendly procedure were revealed as a source of compounds with relevant antioxidant and anticancer activity.

Increasing condom usage for African-American and hispanic young fathers in a community based intervention.

Objectives: This paper investigates a community-based intervention for young fathers, FatherWorks, compared to care-as-usual, 24/7 Dads. We hypothesized that utilizing the FatherWorks intervention (a 15 session parenting intervention, 13 session employment class, paid internship, case management, and access to behavioral health services) will assist in readiness to use condoms and increase condom usage, which may differ by race/ethnicity.Methods: Eligible males (n = 328) were enrolled into a Randomized Control Trial. Participants were 15-24 years old and had fathered one or more children with a female under the age of 21. A survey was taken at baseline and at 15 weeks following the intervention.Results: Analyses of changes indicated that intervention participants improved from the pre-contemplation stage of condom usage towards contemplation, and from preparation to action. The pattern of improvement in the condom use stage of change was different in African-American versus Hispanic participants. Changes in condom use during last intercourse were not significant.Conclusions: Study findings indicate that FatherWorks is successful in increasing the intent to use condoms, with the effect manifesting differently in African-American and Hispanic young fathers. Future work with minority fathers indicates a need for cultural adaptation of the intervention.

Working memory loads differentially influence frame-induced bias and normative choice in risky decision making.

Risky decision making can be biased by several types of contextual factors-in particular, framing of outcomes. A popular explanation for outcome framing effects is based on presumed affective reactions that contribute to accepting sure gains and avoiding sure losses. Other theories propose that selective weighting of information about gains and losses contributes to framing bias. Prior research on framing bias has focused on preferences rather than on decisions in which choices can be classified as advantageous (correct) or disadvantageous (incorrect) by a normative criterion. The current study used a novel hypothetical risky decision making task offering choices between a sure option and a gamble option. The gamble was advantageous or disadvantageous on different trials based on the normative criterion of expected value. Results showed risk avoidance with a gain frame and risk seeking with a loss frame, comparable to findings when choices involve preferences. We also examined the impact of working memory loads of either non-affective stimuli, most likely to interfere with acquisition of choice information, or affective stimuli, which might influence affective processes contributing to framing. The results were that non-affective working memory load produced the greatest framing magnitude, while affective load produced changes in framing magnitude across trials that varied by valence. In addition, only the non-affective load decreased advantageous choices and reduced the accuracy of answers to knowledge probe questions about the choices. The findings are consistent with the notion that framing effects may arise from cognitive non-engagement with the task, rather than arising by way of affective processes. Affective loads had a limited influence on framing and no reliable impact on choice accuracy or choice knowledge, suggesting that the affective loads influenced the weighting of choice information.

Trait anxiety impairs cognitive flexibility when overcoming a task acquired response and a preexisting bias.

Individuals with high trait anxiety tend to be worse at flexibly adapting goal-directed behavior to meet changing demands relative to those with low trait anxiety. Past research on anxiety and cognitive flexibility has used tasks that involve overcoming a recently acquired rule, strategy, or response pattern after an abrupt change in task requirements (e.g., choice X led to positive outcomes but now leads to negative outcomes). An important limitation of this research is that many decision making situations require overcoming a preexisting bias (e.g., deciding whether to withdraw a historically winning investment that has experienced recent losses). In the present study we examined whether anxiety differences in the ability to overcome an acquired response extend to the ability to overcome a preexisting bias, when the bias produces objectively disadvantageous decisions. High anxiety (n = 78) and low anxiety participants (n = 76) completed a commonly used measure of cognitive flexibility, reversal learning, and a novel Framed Gambling Task that assessed the extent to which they could make advantageous decisions when the normatively correct choice was inconsistent with a preexisting framing bias. High anxiety participants showed the expected diminished reversal learning performance and also had poorer ability to make advantageous choices that were inconsistent with the framing bias. Worse performance in the Framed Gambling Task was not driven by poor knowledge of risk contingencies, because high anxiety participants reported the same explicit knowledge as low anxiety participants. Instead, the results suggest high anxiety is associated with general deficits in resolving interference from prepotent responses.

Age-differences in cognitive flexibility when overcoming a preexisting bias through feedback.

INTRODUCTION: Older adults are often worse than younger adults at adapting to changing situational demands, and this difference is commonly attributed to an age-related decline in acquiring and updating information. Previous research on aging and cognitive flexibility has used measures that require adapting to novel associations learned during a laboratory task (e.g., choice X led to positive outcomes but now leads to negative outcomes). However, in everyday life people must frequently overcome associations based on preexisting beliefs and biases (e.g., you like to eat cake, but your doctor said to limit your sugar intake). The goal of the present study was to examine possible age-differences in overcoming a preexisting bias and determine whether age-related changes in the acquisition and updating of information influence this form of flexibility. METHOD: Older (n = 20) and younger (n = 20) adults completed a novel task in which repeated choices were made between a sure option (gain or loss) and one of two risky options that were initially ambiguous. Optimal performance required overcoming a framing bias toward being risk seeking to avoid a sure loss and risk averse when offered a sure gain. Probe questions assessed knowledge of choice outcomes, while skin conductance assessed physiological reactions to choices and choice outcomes. RESULTS: Both older and younger adults demonstrated flexibility by reducing the impact of bias over trials, but younger adults had better performance overall. Age-differences were associated with distinct aspects of processing. Young adults had more precise knowledge of choice outcomes and developed skin conductance responses in anticipation of bad choices that were not apparent in older adults. CONCLUSIONS: Older adults showed significant improvement over trials in their ability to decrease bias-driven choices, but younger showed greater flexibility. Age-differences in task performance were based on differences in learning and corresponding representations of task-relevant information.

Developing scientists in Hispanic substance use and health disparities research through the creation of a national mentoring network.

Hispanics are disproportionately affected by substance use and related health harms yet remain underrepresented across scientific disciplines focused on researching and addressing these issues. An interdisciplinary network of scientists committed to fostering the development of social and biomedical researchers focused on Hispanic substance use and health disparities developed innovative mentoring and career development activities. We conducted a formative evaluation study using anonymous membership and conference feedback data to describe specific mentoring and career development activities developed within the national network. Successful mentoring initiatives and career development activities were infused with cultural and community values supportive of professional integration and persistence. Mentoring initially occurred within an annual national conference and was then sustained throughout the year through formal training programs and informal mentoring networks. Although rigorous evaluation is needed to determine the success of these strategies in fostering long-term career development among scientists conducting Hispanic health and substance use research, this innovative model may hold promise for other groups committed to promoting career development and professional integration and persistence for minority (and non-minority) scientists committed to addressing health disparities.

Colon Cancer Chemoprevention by Sage Tea Drinking: Decreased DNA Damage and Cell Proliferation.

Salvia officinalis and some of its isolated compounds have been found to be preventive of DNA damage and increased proliferation in vitro in colon cells. In the present study, we used the azoxymethane model to test effects of S. officinalis on colon cancer prevention in vivo. The results showed that sage treatment reduced the number of ACF formed only if administered before azoxymethane injection, demonstrating that sage tea drinking has a chemopreventive effect on colorectal cancer. A decrease in the proliferation marker Ki67 and in H2 O2 -induced and azoxymethane-induced DNA damage to colonocytes and lymphocytes were found with sage treatment. This confirms in vivo the chemopreventive effects of S. officinalis. Taken together, our results show that sage treatment prevented initiation phases of colon carcinogenesis, an effect due, at least in part, to DNA protection, and reduced proliferation rates of colon epithelial cell that prevent mutations and their fixation through cell replication. These chemopreventive effects of S. officinalis on colon cancer add to the many health benefits attributed to sage and encourage its consumption.

Effects on Liver Lipid Metabolism of the Naturally Occurring Dietary Flavone Luteolin-7-glucoside.

Disruptions in whole-body lipid metabolism can lead to the onset of several pathologies such as nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs). The present study aimed at elucidating the molecular mechanisms behind the lipid-lowering effects of the flavone luteolin-7-glucoside (L7G) which we previously showed to improve plasma lipid profile in rats. L7G is abundant in plant foods of Mediterranean diet such as aromatic plants used as herbs. Results show that dietary supplementation with L7G for one week induced the expression of peroxisome proliferator-activated receptor-alpha (PPAR-α) and of its target gene carnitine palmitoyl transferase 1 (CPT-1) in rat liver. L7G showed a tendency to decrease the hepatic expression of sterol regulatory element-binding protein-1 (SREBP-1), without affecting fatty acid synthase (FAS) protein levels. Although SREBP-2 and LDLr mRNA levels did not change, the expression of HMG CoA reductase (HMGCR) was significantly repressed by L7G. L7G also inhibited this enzyme's in vitro activity in a dose dependent manner, but only at high and not physiologically relevant concentrations. These results add new evidence that the flavone luteolin-7-glucoside may help in preventing metabolic diseases and clarify the mechanisms underlying the beneficial health effects of diets rich in fruits and vegetables.