Detection of an explosive simulant via electrical impedance spectroscopy utilizing the UiO-66-NH2 metal-organic framework.

Electrical impedance spectroscopy, in conjunction with the metal-organic framework (MOF) UiO-66-NH2, is used to detect trace levels of the explosive simulant 2,6-dinitrotoluene. The combination of porosity and functionality of the MOF provides an effective dielectric structure, resulting in changes of impedance magnitude and phase angle. The promising data indicate that MOFs may be used in low-cost, robust explosive detection devices.

The bromodomain and extra-terminal inhibitor CPI203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors.

Endogenous c-MYC (MYC) has been reported to be a potential pharmacological target to trigger ubiquitous tumor regression of pancreatic neuroendocrine tumors (PanNETs) and lung tumors. Recently inhibitors of bromodomain and extra-terminal (BET) family proteins have shown antitumor effects through the suppression of MYC in leukemia and lymphoma. In this paper, we investigated the antitumor activity of a BET protein bromodomain inhibitor (BETi) CPI203 as a single agent and in combination with rapamycin in human PanNETs. We found that exposure of human PanNET cell lines to CPI203 led to downregulation of MYC expression, G1 cell cycle arrest and nearly complete inhibition of cell proliferation. In addition, overexpression of MYC suppressed the growth inhibition caused by CPI203 and knockdown of MYC phenocopied the effects of CPI203 treatment. These findings indicate that suppression of MYC contributed to the antiproliferative effects of BETi inhibition in human PanNET cells. Importantly, CPI203 treatment enhanced the antitumor effects of rapamycin in PanNET cells grown in monolayer and in three-dimensional cell cultures, as well as in a human PanNET xenograft model in vivo. Furthermore, the combination treatment attenuated rapamycin-induced AKT activation, a major limitation of rapamycin therapy. Collectively, our data suggest that targeting MYC with a BETi may increase the therapeutic benefits of rapalogs in human PanNET patients. This provides a novel clinical strategy for PanNETs, and possibly for other tumors as well.

p53 responsive elements in human retrotransposons.

Long interspersed nuclear elements-1 (L1s) are highly repetitive DNA elements that are capable of altering the human genome through retrotransposition. To protect against L1 retroposition, the cell downregulates the expression of L1 proteins by various mechanisms, including high-density cytosine methylation of L1 promoters and DICER-dependent destruction of L1 mRNAs. In this report, a large number of p53 responsive elements, or p53 DNA binding sites, were detected in L1 elements within the human genome. At least some of these p53 responsive elements are functional and can act to increase the levels of L1 mRNA expression. The p53 protein can directly bind to a short 15-nucleotide sequence within the L1 promoter. This p53 responsive element within L1 is a recent addition to evolution, appearing approximately 20 million years ago. This suggests an interplay between L1 elements, which have a rich history of causing changes in the genome, and the p53 protein, the function of which is to protect against genomic changes. To understand these observations, a model is proposed in which the increased expression of L1 mRNAs by p53 actually increases, rather than decreases, the genomic stability through amplification of p53-dependent processes for genomic protection.

Impact of currently used or potentially useful insecticides for canola agroecosystems on Bombus impatiens (Hymenoptera: Apidae), Megachile rotundata (Hymentoptera: Megachilidae), and Osmia lignaria (Hymenoptera: Megachilidae).

Pest management practices may be contributing to a decline in wild bee populations in or near canola (Brassica napus L.) agroecosystems. The objective of this study was to investigate the direct contact toxicity of five technical grade insecticides--imidacloprid, clothianidin, deltamethrin, spinosad, and novaluron--currently used, or with potential for use in canola integrated pest management on bees that may forage in canola: common eastern bumble bees [Bombus impatiens (Cresson); hereafter bumble bees], alfalfa leafcutting bees [Megachile rotundata (F.)], and Osmia lignaria Cresson. Clothianidin and to a lesser extent imidacloprid were highly toxic to all three species, deltamethrin and spinosad were intermediate in toxicity, and novaluron was nontoxic. Bumble bees were generally more tolerant to the direct contact applications > O. lignaria > leafcutting bees. However, differences in relative toxicities between the three species were not consistent, e.g., whereas clothianidin was only 4.9 and 1.3x more toxic, deltamethrin was 53 and 68x more toxic to leafcutting bees than to bumble bees and O. lignaria, respectively. Laboratory assessment of direct contact toxicity, although useful, is only one measure of potential impact, and mortality under field conditions may differ greatly depending on management practices. Research conducted using only honey bees as the indicator species may not adequately reflect the risk posed by insecticides to wild bees because of their unique biology and differential susceptibility. Research programs focused on determining nontarget impact on pollinators should be expanded to include not only the honey bee but also wild bee species representative of the agricultural system under investigation.

COMT Val158Met and cognition: main effects and interaction with educational attainment.

Studies in children have shown that the genetic influence on cognition is positively correlated with socioeconomic status. Catechol-O-methyltransferase (COMT) Val158Met, a common, functional polymorphism, has been implicated in executive cognition and working memory. Imaging studies have shown that the variant Met allele is associated with more efficient prefrontal cortical processing and better attention but also emotional vulnerability to stress. We hypothesized that COMT Val158Met genotype would interact with years of education (yrs ed), one indicator of socioeconomic adversity, to predict cognitive task performance. We therefore administered the Wechsler Adult Intelligence Scale-Revised (WAIS-R) to 328 community-derived, genotyped, Plains American Indians (mean yrs ed = 12; range = 5-18). We found significant genotypic effects on WAIS-R measures of long-term memory, working memory and attention. The Met allele was associated with improved performance in the Information and Picture Completion subscales; Met/Met homozygotes performed the best. COMT genotype interacted with yrs ed to influence Information and Block Design scores: Met allele carriers' scores improved markedly with increasing yrs ed, whereas the scores of Val/Val individuals were only marginally influenced by yrs ed. There was a crossover of effects at 11-12 yrs ed: in the less educated group, Met allele carriers actually performed worse than Val/Val individuals perhaps because of emotional vulnerability to educational adversity, but in the better educated group, Met allele carriers excelled. Our study in Plains American Indians has shown that COMT Val158Met influences several aspects of cognition and some of its effects are moderated by educational adversity.

Evaluation of sampling methodology for determining the population dynamics of onion thrips (Thysanoptera: Thripidae) in Ontario onion fields.

Onion thrips, Thrips tabaci Lindeman, are an economic pest of alliums worldwide. In Ontario onion-growing regions, seasonal abundance and population trends of onion thrips are not well known. The objectives of this research were to investigate onion thrips population dynamics by using both white sticky traps and plant counts, to gain insight into flight height, and to determine the genus and sex of thrips fauna present in monitored fields. Adult thrips were captured on white sticky traps placed in two commercial onion fields in the Thedford-Grand Bend Marsh region as early as mid-May in 2001, 2002, and 2003. Thrips were not recorded on onion plants in these fields until late June and early July. A comparison of sticky trap captures to plant counts revealed a strong, positive correlation, indicating that sticky traps, which consistently detected thrips earlier than plant counts, could be used instead of plant counts early in the season to monitor onion thrips populations. Pole traps placed in onion and an adjacent soybean, Glycine max (L.) Merr., field revealed that regardless of crop type, most thrips were captured 0.7-0.95 m above the soil surface. During this study, 70% of 137,000 thrips captured on sticky traps and 89% of 1,482 thrips captured in pan traps were female onion thrips. No male onion thrips were identified in this study: most of the remaining thrips were Frankliniella spp.

Neurocognitive impairment due to chronic alcohol consumption in an American Indian community.

OBJECTIVE: Studies have shown that clinically ascertained alcoholics tend to have lower scores than nonalcoholics on cognitive performance tests, particularly the Block Design (BD) and Digit Symbol (DS) tests of the Weschler Adult Intelligence Scale-Revised (WAIS-R). The aim of this study was to determine whether similar differences are found in a community sample of Plains Indian men and women with an episodic pattern of drinking and a high lifetime prevalence of alcoholism (71% for men, 44% for women). METHOD: We administered a truncated form of the WAIS-R to 334 members of a Plains Indian tribe (197 women and 137 men). Blind-rated psychiatric diagnoses were assigned according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III-R) criteria and based on the Schedule for Affective Disorders, Lifetime Version (SADS-L) interview. We compared 68 currently drinking alcoholics (38 men and 30 women), 116 abstaining alcoholics (59 men and 57 women) and 150 nonalcoholics (40 men and 110 women). RESULTS: Current and past heavy drinking had no impact on WAIS-R scores in women. Male alcoholics who were abstinent > or = 2years had similar scores to nonalcoholic men. Male current drinkers showed a trend for lower overall verbal and performance (PIQ) scores and BD performance subtest. Further analysis showed that drinking for > or = 15 years was significantly associated with reduced DS in male current drinkers. CONCLUSIONS: These findings suggest that for the men in this community sample, the impact on PIQ is due to the direct effect of chronic alcohol consumption on cognitive performance and is at least partially reversible after 2 years of abstinence.

Cardiovascular responses of embarrassment and effects of emotional suppression in a social setting.

The cardiovascular effects of embarrassment and of attempts to suppress embarrassment were examined. In 2 studies, embarrassment was associated with substantial increases in systolic and diastolic blood pressure, which monotonically increased over a 2-minute embarrassment period. In contrast, heart rate (HR) rose significantly during the 1st minute of embarrassment but returned to baseline levels during the 2nd minute. This pattern of reactivity may be distinctive. The effects of trying to suppress emotion in an interpersonal situation were also tested. Relative to the no-suppression group, suppression participants showed greater blood pressure during embarrassment and during posttask recovery. Suppression did not significantly affect HR. Possible mechanisms for these results, including passive coping, are discussed. Nonverbal behavior was also examined.

Alcohol use disorders and anxiety disorders: relation to the P300 event-related potential.

BACKGROUND: The robust association of alcoholism with reduced P300 event-related potential amplitude has been largely established in severely affected alcoholics and their offspring. Few studies have examined the relationship of increased arousal, anxiety, and P300. In this study, we sought to determine whether P300 group differences could be discerned in well functioning individuals with less severe forms of alcohol use disorders and anxiety disorders. We were particularly interested in looking at the subgroup of alcohol use disorders accompanied by anxiety disorders. This subgroup has previously been found to have diminished alpha amplitude in the resting EEG. METHODS: Male and female community volunteers (99 unrelated index participants and 78 relatives) and 21 unrelated volunteers from an anxiety disorder clinic were interviewed by using the Schedule for Affective Disorders and Schizophrenia, Lifetime version. Blind-rated lifetime psychiatric diagnoses were assigned according to DSM-III-R criteria. Auditory and visual P300 event-related potentials were elicited with an oddball paradigm and were recorded at the midparietal (Pz) site. RESULTS: As expected, auditory P300 amplitudes were significantly reduced in participants with alcohol use disorders and significantly increased in participants with lifetime anxiety disorders. However, more detailed analysis revealed that, in an apparent paradox, auditory P300 amplitudes were lowest in individuals with comorbid alcohol use and anxiety disorders and highest in individuals with anxiety disorders alone. Visual P300 amplitudes followed the same trends but were generally not significant. CONCLUSIONS: Even in a sample of largely community-ascertained individuals, auditory P300 amplitude is reduced in alcoholics, particularly those with anxiety disorders, and is highest in nonalcoholics with anxiety disorders.

Pyrethroid insecticide residues on vegetable crops.

Pyrethroid insecticides were applied on various vegetable crops as foliar treatments to determine dissipation rates. On Chinese broccoli (Guy Lon), Chinese mustard (Pak Choi) and Chinese cabbage (Kasumi, napa), fenvalerate was persistent with residues of 0.10, 0.14 and 0.11 mg kg-1, respectively, by day 21. Cypermethrin residues on head lettuce were below 0.1 mg kg-1 by day 10 but on the leafier romaine and endive varieties it was more persistent and required 14-19 days to dissipate below this concentration. After three applications, residues of cypermethrin in harvested carrots and of permethrin in eggplant were not detected on the day of application. On asparagus, deltamethrin and cypermethrin residues declined to less than 0.1 mg kg-1 by days 1 and 2, respectively; permethrin was more persistent, requiring more than 2 days to decline to less than 0.1 mg kg-1. Deltamethrin on dry (cooking) and Spanish onions was not detected on the day of application. On tomatoes, the concentration of permethrin was 0.093 mg kg-1 on the day of application and declined to about 0.05 mg kg-1 after 2-4 days. In general, permethrin, cypermethrin and deltamethrin residues declined to acceptable concentrations within an acceptable pre-harvest interval. Fenvalerate may be too persistent on these speciality crops unless a maximum residue limit > 0.1 mg kg-1 is permitted.

Does a reduced sensitivity to bitter taste increase the risk of becoming nicotine addicted?

Cigarette smoking appears to be on the increase in adolescents. The initiation of regular smoking nearly always begins before adulthood. It is therefore crucial to find ways of identifying those children most vulnerable to nicotine addiction and prioritizing them for preventive measures. We hypothesized that individuals who, in a simple taste test, perceive phenylthiocarbamide (PTC) as bitter may find the taste of cigarettes aversively bitter and could therefore have a reduced vulnerability to nicotine addiction compared to nontasters, who would be the group at greater risk of addiction. We studied 242 Plains American Indians, 136 women and 106 men aged 18-59 years, and found that (allowing for gender differences and the possible direct effects of smoking on taste) the proportion of PTC nontasters to tasters in smokers, even light smokers, was significantly greater than in both nonsmokers and social smokers (chi2= 15.875, 4 df; P=.003), suggesting that nontasters, who are not aversive to the bitter taste of cigarettes, may be more at risk for heavy smoking and therefore more vulnerable to nicotine addiction.

Pursuit of optimal carbohydrate-based anticancer vaccines: preparation of a multiantigenic unimolecular glycopeptide containing the Tn, MBr1, and Lewis(y) antigens.

A novel preparation of nonnatural glycoamino acids starting from n-pentenyl glycosides is described. The approach involves a Horner-Emmons olefination with a suitably protected glycine-derived phosphonate, followed by catalytic asymmetric hydrogenation, which proceeds with excellent diastereomeric selectivity. The synthetic methodology was useful for the preparation of glycoamino acids containing the Tn antigen, the MBr1 antigen (Globo-H), the Le(y) antigen, and lactose. These glycoamino acids can also serve as units for peptide synthesis. The synthesis of polyvalent glycopeptides containing three different antitumor antigens is described (28 and 29), and these have been prepared for conjugation to carrier protein in order to access the immunogenicity for tumor immunotherapy applications.

Spontaneous allocation of visual attention: dominant role of uniqueness.

Common sense suggests that unique or abruptly changing (transient) elements in a visual scene often draw attention involuntarily. Visual search studies paint a seemingly different picture, however Unique items usually draw attention involuntarily only when observers seek a unique target. One type of transient--abrupt onsets--draws attention involuntarily, but only when the observer is seeking an onset (Folk, Remington, & Johnston, 1992). One way of reconciling common-sense with these findings is to suppose that when people view a scene with no specific goal or task, they adopt a default set, which might prioritize novelty and/or transients. In two experiments, 336 subjects saw a single display of six items for 900 msec, expecting to have to describe it (Experiment 1) or make an aesthetic judgment about it (Experiment 2). One item in the display was either uniquely flashing (surrounded by static items) or uniquely static (surrounded by flashing items). In both studies, the unique item, even if static, was more often reported than the non-unique item, with flashing items enjoying an additional advantage.

Psychophysiological responses to imagined infidelity: the specific innate modular view of jealousy reconsidered.

Three studies measured psychophysiological reactivity (heart rate, blood pressure, and electrodermal activity) while participants imagined a mate's infidelity. The specific innate modular theory of gender differences in jealousy hypothesizes that men are upset by sexual infidelity and women are upset by emotional infidelity, because of having faced different adaptive challenges (cuckoldry and loss of a mate's resources, respectively). This view was not supported. In men, sexual-infidelity imagery elicited greater reactivity than emotional-infidelity imagery. But, sexual imagery elicited greater reactivity even when infidelity was not involved, suggesting that the differential reactivity may not specifically index greater jealousy. In two studies with reasonable power, women did not respond more strongly to emotional infidelity. Moreover, women with committed sexual relationship experience showed reactivity patterns similar to those of men. Hypothetical infidelity self-reports were unrelated to reactivity.

Association of low-voltage alpha EEG with a subtype of alcohol use disorders.

BACKGROUND: Neurophysiological traits may identify more homogeneous subgroups of alcoholics. Such discoveries could yield information regarding pathophysiological development, leading to more specific preventive measures and treatments. In an earlier study of 127 individuals, 59 of whom were unrelated, we found that a heritable resting Electroencephalographic (EEG) phenotype, i.e., the low-voltage alpha (LVA) trait, was associated with alcohol use disorders and anxiety disorders. METHODS: We evaluated these findings using an independent, similarly established, dataset of 120 subjects. We also extended the study to a larger set of 149 unrelated individuals from a total sample of 247 subjects for whom psychiatric diagnoses and resting EEG phenotypes were available. Blind-rated psychiatric diagnoses were formulated according to DSM-III-R criteria. RESULTS: In the replication sample, the LVA trait was again more common among subjects with anxiety disorders than among those without. In the total group of unrelated individuals, alcoholics were significantly (3 times) more likely to show the LVA trait than were nonalcoholics. Again, individuals with anxiety disorders were significantly (3 times) more likely to exhibit the LVA trait than were those without anxiety disorders. Of 11 unrelated alcoholics with anxiety disorders, seven showed the LVA trait. It was specifically the LVA trait and not low-amplitude alpha activity that was associated with alcohol use disorders. CONCLUSIONS: The results of this replication study and the analysis of the total sample of unrelated individuals support an association between LVA EEG and the subtype of alcohol use disorders associated with anxiety disorders. The LVA phenotype may be a vulnerability factor for alcohol use disorders and anxiety disorders.

Mapping an interface of SecY (PrlA) and SecE (PrlG) by using synthetic phenotypes and in vivo cross-linking.

SecY and SecE are integral cytoplasmic membrane proteins that form an essential part of the protein translocation machinery in Escherichia coli. Sites of direct contact between these two proteins have been suggested by the allele-specific synthetic phenotypes exhibited by pairwise combinations of prlA and prlG signal sequence suppressor mutations in these genes. We have introduced cysteine residues within the first periplasmic loop of SecY and the second periplasmic loop of SecE, at a specific pair of positions identified by this genetic interaction. The expression of the cysteine mutant pair results in a dominant lethal phenotype that requires the presence of DsbA, which catalyzes the formation of disulfide bonds. A reducible SecY-SecE complex is also observed, demonstrating that these amino acids must be sufficiently proximal to form a disulfide bond. The use of cysteine-scanning mutagenesis enabled a second contact site to be discovered. Together, these two points of contact allow the modeling of a limited region of quaternary structure, establishing the first characterized site of interaction between these two proteins. This study proves that actual points of protein-protein contact can be identified by using synthetic phenotypes.

Chlorpyrifos: a ten-year US poison center exposure experience.

We performed a retrospective review of data based on poison center exposure inquiries related to chlorpyrifos (CP) and the corresponding poison center-determined medical outcomes reported to the Toxic Exposure Surveillance System (TESS) of the American Association of Poison Control Centers. Ten y (1985-1994) of TESS data were obtained. Medical outcomes representing all inquiries, accidental/unintentional inquiries, and intentional/suicidal inquiries were tabulated. Published TESS data was also tabulated to allow comparison of CP exposure inquiries to all non-pharmaceutical and insecticides/pesticides exposure inquiries for like time periods. Frequency of antidote use, product sales data, CP-related fatality reports, and pertinent issues related to telephone derived surveillance data were also reviewed; 36, 183 CP exposure inquiries were identified. Of all CP exposure inquiries, 27, 473 (75.9%) were assessed as having no significant health consequences; 4,511 (12.5%) outcomes were judged unrelated and 2,980 (8.2%) were unable to be followed. Reported significant medical outcomes for the remaining exposure inquiries were moderate 1,092 (3.0%), major 119 (0.3%) and death 8 (0.02%). Considering only calls with outcomes judged causally related to CP, where a given level of effect could reasonably be determined, 95.8% (27,473/28,692) of these calls resulted in no significant health effects. Use of antidotes specific to organophosphates were infrequent [atropine, 1.0% (385) and 2-PAM, 0.5% (177) of all cases respectively]. Despite the number of reported CP exposure inquiries, relatively few resulted in outcomes of consequence. TESS data suggested that the majority of patients undergoing medical evaluation and/or treatment after a suspected CP exposure do not require specific antidotes. TESS data serves as a useful first step in evaluating product safety. Assessment of product toxicity requires additional investigation of reported adverse effects and circumstances related to the incident.

Can a machine tickle?

It has been observed at least since the time of Aristotle that people cannot tickle themselves, but the reason remains elusive. Two sorts of explanations have been suggested. The interpersonal explanation suggests that tickling is fundamentally interpersonal and thus requires another person as the source of the touch. The reflex explanation suggests that tickle simply requires an element of unpredictability or uncontrollability and is more like a reflex or some other stereotyped motor pattern. To test these explanations, we manipulated the perceived source of tickling. Thirty-five subjects were tickled twice--once by the experimenter, and once, they believed, by an automated machine. The reflex view predicts that our "tickle machine" should be as effective as a person in producing laughter, whereas the interpersonal view predicts significantly attenuated responses. Supporting the reflex view, subjects smiled, laughed, and wiggled just as often in response to the machine as to the experimenter. Self-reports of ticklishness were also virtually identical in the two conditions. Ticklish laughter evidently does not require that the stimulation be attributed to another person, as interpersonal accounts imply.