Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context

The memory for a new episode is formed immediately upon experience and can last up to a lifetime. It has been shown that the hippocampal network plays a fundamental role in the rapid acquisition of a memory of a one-time experience, in which the novelty component of the experience promotes the prompt formation of the memory. However, it remains unclear which neural circuits convey the novelty signal to the hippocampus for the single-trial learning. Here, we show that during encoding neuromodulatory input from locus coeruleus (LC) to CA3, but not CA1 or to the dentate gyrus, is necessary to facilitate novel contextual learning. Silencing LC activity during exposure to a novel context reduced subsequent reactivation of the engram cell ensembles in CA3 neurons and in downstream CA1 upon reexposure to the same context. Calcium imaging of the cells reactivated in both novel and familiar contexts revealed that suppression of LC inputs at the time of encoding resulted in more variable place fields in CA3 neurons. These results suggest that neuromodulatory input from LC to CA3 is crucial for the formation of a persistent memory in the hippocampus

Safety and pharmacokinetics of motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study

Background: This phase 1b study assessed the maximum tolerated dose (MTD), safety, and pharmacokinetics of motesanib (a small-molecule antagonist of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) administered once daily (QD) or twice daily (BID) in combination with erlotinib and gemcitabine in patients with solid tumors. Methods: Patients received weekly intravenous gemcitabine (1000 mg/m2) and erlotinib (100 mg QD) alone (control cohort) or in combination with motesanib (50 mg QD, 75 mg BID, 125 mg QD, or 100 mg QD; cohorts 1-4); or erlotinib (150 mg QD) in combination with motesanib (100 or 125 mg QD; cohorts 5 and 6). Results: Fifty-six patients were enrolled and received protocol-specified treatment. Dose-limiting toxicities occurred in 11 patients in cohorts 1 (n = 2), 2 (n = 4), 3 (n = 3), and 6 (n = 2). The MTD of motesanib in combination with gemcitabine and erlotinib was 100 mg QD. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Frequently occurring motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3. The pharmacokinetics of motesanib was not markedly affected by coadministration of gemcitabine and erlotinib, or erlotinib alone. Erlotinib exposure, however, appeared lower after coadministration with gemcitabine and/or motesanib. Of 49 evaluable patients, 1 had a confirmed partial response and 26 had stable disease. Conclusions: Treatment with motesanib 100 mg QD plus erlotinib and gemcitabine was tolerable. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone.Dusan Kotasek, Niall Tebbutt, Jayesh Desai, Stephen Welch, Lillian L Siu, Sheryl McCoy, Yu-Nien Sun, Jessica Johnson, Adeboye H Adewoye and Timothy Pric

Effect of solvent and extraction temperatures on the antioxidant potential of traditional stoned table olives “alcaparras”

This paper reports the first approach to the antioxidant potential evaluation of traditional stoned table olives ‘‘alcaparras’’. This kind of olives are largely produced and consumed in Trás-os-Montes region (Northeast of Portugal). Different solvents and temperature extraction conditions were employed in order to achieve the best method to obtain phenolic compounds and a higher antioxidant activity. The optimum method (water at boiling temperature) was applied on 10 samples from the traditional market. The total phenol content ranged between 5.58mg gallic acid equivalents (GAE)/g and 29.88mg GAE/g and effective concentration (EC50) values were in the range 0.36–1.64 and 0.34–1.72 mg/mL for reducing power and radical scavenging effect, respectively. A significantly negative linear regression was observed between the total phenol content found in the samples and its antioxidant activity

Phytopharmacologic preparations as predictors of plant bioactivity: A particular approach to Echinacea purpurea (L.) Moench antioxidant properties

Objective A large body of evidence has confirmed a multitude of health benefits of plant products and their derived formulations. Echinacea purpurea (L.) Moench is a good example, widely used due to its therapeutic properties. In the present study, the chemical composition of the different samples and antioxidant properties of E. purpurea hydroethanolic and aqueous extracts obtained from dry or fresh raw material were evaluated and compared with dietary supplements based on the same plant (tablets and syrup), to determine the most active phytopharmacologic preparation or formulation. Methods Chemical composition of the different samples was assessed through the determination of free sugars, organic acids and tocopherols. The in vitro antioxidant properties were determined using four assays: 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radicals scavenging activity, reducing power, inhibition of b-carotene bleaching and inhibition of lipid peroxidation by thiobarbituric acid reactive substances (TBARS) assay. Total phenolics and flavonoids were also determined. Results Overall, the hydroethanolic extract of fresh plant revealed the highest activity, directly related with its higher contents in phenolic (229.22 ± 4.38 mg gallic acid equivalent [GAE]/mL), flavonoids (124.83 ± 7.47 mg GAE/mL), organic acids (8.89 ± 0.10 g/100 g), and tocopherols (4.55 ± 0.02 mg/100 g). Tablets followed by syrup revealed the worst effect, positively correlated with the lowest abundance in bioactive molecules. The weak in vitro antioxidant potential of commercial phytopharmacologic formulations could be related to their chemical composition, including the addition of excipients. Conclusion Further studies are necessary to deepen knowledge on this area, namely focusing on in vivo experiments, to establish upcoming guidelines to improve the quality and bioavailability of phytopharmacologic formulations.The authors are grateful to Foundation for Science and Technology (FCT, Portugal) for financial support to the research center CIMO (strategic project PEst-OE/AGR/UI0690/2014) and L. Barros researcher contract under “Programa Compromisso com Ciência – 2008”

RAD51 foci as a biomarker predictive of platinum chemotherapy response in ovarian cancer

PURPOSE: To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples. EXPERIMENTAL DESIGN: RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n = 5), organoids (n = 11), and formalin-fixed, paraffin-embedded tumor samples (discovery n = 31, validation n = 148). Samples were defined as RAD51-High if \u3e10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated. RESULTS: RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r = 0.96, P = 0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P \u3c 0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR, 5.28; P \u3c 0.001) and to be platinum-sensitive (RR, ∞; P = 0.05). The RAD51 score was predictive of chemotherapy response score [AUC, 0.90; 95% confidence interval (CI), 0.78-1.0; P \u3c 0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR, ∞; P \u3c 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR, 0.53; 95% CI, 0.33-0.85; P \u3c 0.001) and overall survival (HR, 0.43; 95% CI, 0.25-0.75; P = 0.003) than RAD51-High status. CONCLUSIONS: RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials

Detection of large deletions in the LDL receptor gene with quantitative PCR methods

BACKGROUND: Familial Hypercholesterolemia (FH) is a common genetic disease and at the molecular level most often due to mutations in the LDL receptor gene. In genetically heterogeneous populations, major structural rearrangements account for about 5% of patients with LDL receptor gene mutations. METHODS: In this study we tested the ability of two different quantitative PCR methods, i.e. Real-Time PCR and Multiplex Ligation-Dependent Probe Amplification (MLPA), to detect deletions in the LDL receptor gene. We also reassessed the contribution of major structural rearrangements to the mutational spectrum of the LDL receptor gene in Denmark. RESULTS: With both methods it was possible to discriminate between one and two copies of the LDL receptor gene exon 5, but the MLPA method was cheaper, and it was far more accurate and precise than Real-Time PCR. In five of 318 patients with an FH phenotype, MLPA analysis revealed five different deletions in the LDL receptor gene. CONCLUSION: The MLPA method was accurate, precise and at the same time effective in screening a large number of FH patients for large deletions in the LDL receptor gene

Phytochemical content and antioxidant activity of grapefruit (Star Ruby): A comparison between fresh freeze-dried fruits and different powder formulations

[EN] Different grapefruit powders obtained by freeze drying and spray drying with prior addition of shell materials (arabic gum and bamboo fiber) were studied in order to evaluate the effect of these preservation processes on the retention of antioxidants, in comparison with the freeze-dried fruit with no carriers added. Freeze-dried samples showed above 90% retention of these phytochemicals, while spray-dried samples presented good retention of vitamins but a sharp decrease in of phenolic compounds. Pearson's correlation analysis showed that the most significant contribution to DPPH scavenging activity and inhibition of &#946;-carotene bleaching was provided by phenolic compounds, mostly flavonoids, while the contribution to the reducing power was due to ascorbic acid and &#945;-tocopherol. Therefore, the loss of these compounds in the spray-dried samples resulted in products with lower antioxidant activity. Naringin and narirutin were the major phenolic compounds in all grapefruit samples, although other flavanones present in lower concentration, like hesperidin, neohesperidin didymin, poncirin or melitidin, also showed high correlations with the antioxidant value of the samples.The authors thank the Ministerio de Economia y Competitividad for the financial support given throughout the Project AGL 2012-39103, and to the Foundation for Science and Technology and FEDER under Program PT2020 for financial support to CIMO (UID/AGR/00690/2013), and L. Barros (SFRH/BPD/107855/2015) grant. To POCI-01-0145-FEDER-006984 (LA LSRE-LCM), funded by ERDF, through POCI-COMPETE2020 and FCT.Agudelo-Sterling, C.; Barros, L.; Santos-Buelga, C.; Martínez Navarrete, N.; Ferreira, ICFR. (2017). Phytochemical content and antioxidant activity of grapefruit (Star Ruby): A comparison between fresh freeze-dried fruits and different powder formulations. LWT - Food Science and Technology. 80:106-112. https://doi.org/10.1016/j.lwt.2017.02.006S1061128

The frequency of cyclonic wind storms shapes tropical forest dynamism and functional trait dispersion

As cyclonic wind storms (hurricanes and typhoons) increase in frequency and intensity with climate change, it is important to understand their effects on the populations and communities of tropical trees they impact. Using tree demographic data from four large, tropical forest dynamics plots that differ in cyclonic storm frequency, we compare tree population and community dynamics. Additionally, we assess the effect of cyclonic storms on three functional traits, specific leaf area, wood density, and tree height of the dynamic tree assemblages. Mortality, growth and recruitment rates and the intrinsic rates of population growth of species differed across the plots, and were most dynamic, especially for stems 1–2 cm in diameter, at the plot which had an intermediate level of cyclonic storm frequency. Functional assemblages of species had the greatest degree of temporal variation in relation to disturbance, as measured by the change in functional divergence for the two plots with more intermediate cyclonic storm recurrence. Therefore, cyclonic storms affecting these plots generally have a greater effect on forest composition and dynamism than comparable cyclonic storms do on the plot which experiences cyclonic storms more frequently. Thus, we provide some evidence that community-wide demographic resistance to cyclonic storms is generally lower at an intermediate frequency of storms. While cyclonic storm strength and timing are important determinants of the within forest variation in tree dynamics and functional trait assemblages, we also show that cyclonic storm timing and frequency shapes tropical forest dynamics and functional composition across forests. We conclude that, over a given time interval, sites with intermediate levels of damaging cyclonic wind disturbance express a greater potential for life-history variation in the forest community, when compared to sites with less or more frequent disturbance