Double layer effects in voltammetric measurements with scanning electrochemical microscopy (SECM)

Scanning electrochemical microscopy (SECM) operating as a variable gap ultra-thin layer twin-working electrode cell, has long been recognised as a powerful technique for investigating fast kinetics (heterogeneous electron transfer and homogeneous reactions coupled to electron transfer) as a consequence of high mass transport rates between the working electrodes when biased to promote redox shuttling. Recently, SECM has advanced technically and nanogap cells with dimensions on the 10s of nm scale have been reported. In this paper, we consider double layer effects on voltammetric measurements in this configuration, outlining a comprehensive model that solves the Nernst-Planck equation and Poisson equation with charged interfaces. For supporting electrolyte concentrations that have been used for such measurements (50 mM and 100 mM), it is shown that for typical electrode charges and charge on the glass insulator that encases the ultramicroelectrode (UME) tip used in SECM, there are profound effects on the voltammetric wave-shapes for redox reactions of charged redox couples, in the common modes used to study electron transfer kinetics, namely the tip-voltammetry (feedback) mode and substrate-voltammetry (substrate-generation/tip-collection and competition) modes. Using the reduction and oxidation of a singly charged redox species to a neutral and doubly charged species, respectively, as exemplar systems, it is shown that the charge on the electrodes can greatly distort the voltammetric wave-shape, while charge on the glass that surrounds the UME tip can affect the limiting current. Analysis of SECM voltammograms using methods that do not account for double layer effects will thus result in significant error in the kinetic values derived and tip-substrate distances that have to be estimated from limiting currents in SECM. The model herein provides a framework that could be developed for further studies with nanogap-SECM (e.g. consideration of alternative models for the electrical double layer, other supporting electrolyte concentrations, potential of zero charge on the electrodes and charges on the redox couples). The model results presented are shown to qualitatively match to SECM voltammetric features from experimental data in the literature, and are further supported by experimental data for redox processes of tetrathiafulvalene (TTF), namely the TTF/TTF+ and TTF+/TTF2+ redox couples. This serves to demonstrate the immediate practical application of some of the ideas presented herein. For future applications of SECM, the use of different supporting electrolyte concentrations and a range of tip-substrate separations may allow the determination of both electron transfer kinetics and double layer properties

The Role of Endophytic Fungi in the Anticancer Activity of Morinda citrifolia

We hypothesize that the fungal endophytes of noni may possibly play a role in its overall pharmacological repertoire, especially since the perceived efficacy of the fruit in ethnomedicinal use is associated with the fermented juice. The foremost goal of this study is to explore the role of endophyte-derived secondary metabolites in the purported anticancer properties of noni. To that end, culturable endophytic fungi resident within the healthy leaves and fruit of the plant were isolated and identified by molecular sequence analysis of the 5.8S gene and internal transcribed spacers (ITS). Purified organisms were subjected to in vitro fermentation in malt extract broth for 8 weeks under anaerobic conditions at room temperature (25°C), in order to simulate the conditions under which traditional fermented noni juice is prepared. The cytotoxic potential of organic extracts derived from the fermented broths of individual endophytes was then tested against three major cancers that afflict humans. Twelve distinct endophytic fungal species were obtained from the leaves and 3 from the fruit. Three of the leaf endophytes inhibited the growth of human carcinoma cell lines LU-1 (lung), PC-3 (prostate), and MCF-7 (breast) with IC50 values of ≤10 μg/mL

Peanut allergy:effect of environmental peanut exposure in children with filaggrin loss-of-function mutations

BackgroundFilaggrin (FLG) loss-of-function mutations lead to an impaired skin barrier associated with peanut allergy. Household peanut consumption is associated with peanut allergy, and peanut allergen in household dust correlates with household peanut consumption.ObjectiveWe sought to determine whether environmental peanut exposure increases the odds of peanut allergy and whether FLG mutations modulate these odds.MethodsExposure to peanut antigen in dust within the first year of life was measured in a population-based birth cohort. Peanut sensitization and peanut allergy (defined by using oral food challenges or component-resolved diagnostics [CRD]) were assessed at 8 and 11 years. Genotyping was performed for 6 FLG mutations.ResultsAfter adjustment for infantile atopic dermatitis and preceding egg skin prick test (SPT) sensitization, we found a strong and significant interaction between natural log (ln [loge]) peanut dust levels and FLG mutations on peanut sensitization and peanut allergy. Among children with FLG mutations, for each ln unit increase in the house dust peanut protein level, there was a more than 6-fold increased odds of peanut SPT sensitization, CRD sensitization, or both in children at ages 8 years, 11 years, or both and a greater than 3-fold increased odds of peanut allergy compared with odds seen in children with wild-type FLG. There was no significant effect of exposure in children without FLG mutations. In children carrying an FLG mutation, the threshold level for peanut SPT sensitization was 0.92 μg of peanut protein per gram (95% CI, 0.70-1.22 μg/g), that for CRD sensitization was 1.03 μg/g (95% CI, 0.90-1.82 μg/g), and that for peanut allergy was 1.17 μg/g (95% CI, 0.01-163.83 μg/g).ConclusionEarly-life environmental peanut exposure is associated with an increased risk of peanut sensitization and allergy in children who carry an FLG mutation. These data support the hypothesis that peanut allergy develops through transcutaneous sensitization in children with an impaired skin barrier

Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1)

Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark cancer phenotypes. This has led to the identification and development of small molecules with spliceosome-modulating activity as potential anticancer agents. Jerantinine A (JA) is a novel indole alkaloid which displays potent anti-proliferative activities against human cancer cell lines by inhibiting tubulin polymerization and inducing G2/M cell cycle arrest. Using a combined pooled-genome wide shRNA library screen and global proteomic profiling, we showed that JA targets the spliceosome by up-regulating SF3B1 and SF3B3 protein in breast cancer cells. Notably, JA induced significant tumor-specific cell death and a significant increase in unspliced pre-mRNAs. In contrast, depletion of endogenous SF3B1 abrogated the apoptotic effects, but not the G2/M cell cycle arrest induced by JA. Further analyses showed that JA stabilizes endogenous SF3B1 protein in breast cancer cells and induced dissociation of the protein from the nucleosome complex. Together, these results demonstrate that JA exerts its antitumor activity by targeting SF3B1 and SF3B3 in addition to its reported targeting of tubulin polymerization

No short-term contingency between grooming and food tolerance in Barbary macaques (Macaca sylvanus)

The exchange services such as allo-grooming, allo-preening, food tolerance and agonistic support has been observed in a range of species. Two proximate mechanisms have been proposed to explain the exchanges of services in animals. First, an animal can give a service to a partner depending on how the partner behaved toward it in the recent past. This mechanism is usually tested by examining the within-dyad temporal relation between events given and received over short time periods. Second, the partner choice mechanism assumes that animals give favours toward specific partners but not others, by comparing how each partner behaved toward them over longer time frames. As such, the partner choice mechanism does not make specific predictions on a temporal contingency between services received and given over short time frames. While there is evidence for a long-term positive correlation between services exchanged in animals, results for short-term contingencies between services given and received are mixed. Our study investigated the exchange of grooming for food tolerance in a partially-provisioned group of Barbary macaques, by analysing the short-term contingency between these events. Tolerance over food was compared immediately after grooming and in control condition, using food of different shareability. We found no evidence that grooming increases food tolerance or decrease aggression around food in the short term. Food tolerance was affected by the shareability of the food and the sex of the partners. The exchanges of grooming and food tolerance in non-human primates may be little affected by recent single events. We suggest that long-term exchanges between services given and received and social partner choice may play a more important role in explaining social interactions than short-term contingent events

Sperm storage by males causes changes in sperm phenotype and influences the reproductive fitness of males and their sons

Recent studies suggest that environmentally induced effects on sperm phenotype can influence offspring phenotype beyond the classic Mendelian inheritance mechanism. However, establishing whether such effects are conveyed purely through ejaculates, independently of maternal environmental effects, remains a significant challenge. Here, we assess whether environmentally induced effects on sperm phenotype affects male reproductive success and offspring fitness. We experimentally manipulated the duration of sperm storage by males, and thus sperm age, in the internally fertilizing fish Poecilia reticulata. We first confirm that sperm ageing influences sperm quality and consequently males reproductive success. Specifically, we show that aged sperm exhibit impaired velocity and are competitively inferior to fresh sperm when ejaculates compete to fertilize eggs. We then used homospermic (noncompetitive) artificial insemination to inseminate females with old or fresh sperm and found that male offspring arising from fertilizations by experimentally aged sperm suffered consistently impaired sperm quality when just sexually mature (four months old) and subsequently as adults (13 months old). Although we have yet to determine whether these effects have a genetic or epigenetic basis, our analyses provide evidence that environmentally induced variation in sperm phenotype constitutes an important source of variation in male reproductive fitness that has far reaching implications for offspring fitness

Research-based versus clinical serum creatinine measurements and the association of acute kidney injury with subsequent kidney function: findings from the Chronic Renal Insufficiency Cohort study.

Background:Observational studies relying on clinically obtained data have shown that acute kidney injury (AKI) is linked to accelerated chronic kidney disease (CKD) progression. However, prior reports lacked uniform collection of important confounders such as proteinuria and pre-AKI kidney function trajectory, and may be susceptible to ascertainment bias, as patients may be more likely to undergo kidney function testing after AKI. Methods:We studied 444 adults with CKD who participated in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study and were concurrent members of a large integrated healthcare delivery system. We estimated glomerular filtration rate (eGFR) trajectories using serum creatinine measurements from (i) the CRIC research protocol (yearly) and (ii) routine clinical care. We used linear mixed effects models to evaluate the associations of AKI with acute absolute change in eGFR and post-AKI eGFR slope, and explored whether these varied by source of creatinine results. Models were adjusted for demographic characteristics, diabetes status and albuminuria. Results:During median follow-up of 8.5 years, mean rate of eGFR loss was -0.31 mL/min/1.73 m2/year overall, and 73 individuals experienced AKI (55% Stage 1). A significant interaction existed between AKI and source of serum creatinine for acute absolute change in eGFR level after discharge; in contrast, AKI was independently associated with a faster rate of eGFR decline (mean additional loss of -0.67 mL/min/1.73 m2/year), which was not impacted by source of serum creatinine. Conclusions:AKI is independently associated with subsequent steeper eGFR decline regardless of the serum creatinine source used, but the strength of association is smaller than observed in prior studies after taking into account key confounders such as pre-AKI eGFR slope and albuminuria

The Multifaceted Appearance of Supratentorial Ependymoma with ZFTA-MAML2 Fusion

Ependymomas are glial neoplasms with a wide morphological spectrum. The majority of supratentorial ependymomas are known to harbor ZFTA fusions, most commonly to RELA. We present an unusual case of a 9-year-old boy with a supratentorial ependymoma harboring a noncanonical ZFTA-MAML2 fusion. This case had unusual histomorphological features lacking typical findings of ependymoma and bearing resemblance to a primitive neoplasm with focal, previously undescribed myogenic differentiation. We discuss the diagnostic pitfalls in this case and briefly review the histological features of ependymoma with noncanonical gene fusions. Our report underscores the importance of molecular testing in such cases to arrive at the correct diagnosis. Supratentorial ependymomas with noncanonical fusions are rare, and more studies are necessary for better risk stratification and identification of potential treatment targets

Relationships Between Self-Reported Smoking, Household Environmental Tobacco Smoke Exposure and Depressive Symptoms in a Pregnant Minority Population

This study sought to examine relationships between depressive symptoms and prenatal smoking and/or household environmental tobacco smoke exposure (HHETSE) among urban minority women. We analyzed private, audio computer-assisted self interview data from a clinic-based sample of 929 minority pregnant women in Washington, DC. Depressive symptoms were assessed via the Beck Depression Inventory Fast Screen. HH-ETSE, current smoking, and former smoking were assessed via self-report. Depression levels and demographic characteristics were compared: (1) among nonsmokers, for those reporting HH-ETSE versus no HH-ETSE; and (2) among smokers, for those reporting current smoking (in last 7 days) versus former smokers. Measures associated with HH-ETSE/current smoking in bivariate analysis at P\0.20 were included in adjusted logistic regression models. HH-ETSE, as a possible indicator of a social smoking network, was assessed as a mediator for the relationship between depression and current smoking. Results: Non-smokers reporting moderate-to-severe depressive symptoms showed significantly higher adjusted odds of prenatal HH-ETSE (AOR 2.5, 95% CI [1.2, 5.2]). Smokers reporting moderate-to-severe or mild depressive symptoms showed significantly higher adjusted odds of current smoking (AOR 1.9, 95% CI [1.1, 3.5] and AOR 1.8, 95% CI [1.1, 3.1], respectively). Among smokers, HH-ETSE was a significant mediator for the association between moderate-to-severe symptoms and current smoking. In conclusion, health care providers should be aware that depressed urban minority women are at risk of continued smoking/HH-ETSE during pregnancy. Interventions designed to encourage behavior change should include screening for depression, and build skills so that women are better able to address the social environment