Response Inhibition Deficits in Women with the FMR1 Premutation are Associated with Age and Fall Risk.

One in 113-178 females worldwide carry a premutation allele on the FMR1 gene. The FMR1 premutation is linked to neurocognitive and neuromotor impairments, although the phenotype is not fully understood, particularly with respect to age effects. This study sought to define oculomotor response inhibition skills in women with the FMR1 premutation and their association with age and fall risk. We employed an antisaccade eye-tracking paradigm to index oculomotor inhibition skills in 35 women with the FMR1 premutation and 28 control women. The FMR1 premutation group exhibited longer antisaccade latency and reduced accuracy relative to controls, indicating deficient response inhibition skills. Longer response latency was associated with older age in the FMR1 premutation and was also predictive of fall risk. Findings highlight the utility of the antisaccade paradigm for detecting early signs of age-related executive decline in the FMR1 premutation, which is related to fall risk. Findings support the need for clinical prevention efforts to decrease and delay the trajectory of age-related executive decline in women with the FMR1 premutation during midlife.

Double Hydrophosphorylation of Nitriles Catalyzed by Rare-Earth-Metal Lanthanum.

A high-yielding and atom-efficient protocol for the double hydrophosphorylation of nitriles using a lanthanum-based N,N-dimethylbenzylamine complex (La(DMBA)3) as a precatalyst is reported. This method provides a straightforward and convenient approach for the synthesis of biologically important organophosphorus compounds known as N-(α-phosphoryl)amidophosphates in good to excellent yields. Nitriles with a broad range of additional functionality were tolerated, including those with halides, ethers, amines, and pyridyl groups.

An algorithm to minimize the number of blocks in incomplete block designs.

Incomplete block designs are experimental designs in which a subset of treatments are included in each block. The researcher must decide which conditions are assigned to each block. This design concept is quite general. At the level of the experiment, a treatment is a condition in an experiment, blocks are different groups of subjects, and the researcher must decide how to assign a subset of conditions to each block of subjects. At the level of the subject, the treatments correspond to individual stimuli, blocks correspond to experimental trials, and the researcher must decide which subset of stimuli to include in each trial. In this article, we present an efficient algorithm that assigns treatments to blocks in an incomplete block design according to two criteria: Each pair of treatments must appear together in at least one block, and the number of blocks in the experiment is minimized. We discuss details and applications of the algorithm and provide software and a web application to generate designs according to the needs of the researcher.

A novel eye-tracking paradigm for indexing social avoidance-related behavior in fragile X syndrome.

Fragile X syndrome (FXS) is characterized by hallmark features of gaze avoidance, reduced social approach, and social anxiety. The development of therapeutics to manage these symptoms has been hindered, in part, by the lack of sensitive outcome measures. This study investigated the utility of a novel eye-tracking paradigm for indexing social avoidance-related phenotypes. Adolescent/young adult-aged males with FXS (n = 24) and typical development (n = 23) participated in the study. Participants viewed faces displaying direct or averted gaze and the first fixation duration on the eyes was recorded as an index of initial stimulus registration. Fixation durations did not differ across the direction of gaze conditions in either group, although the control group showed longer initial fixations on the eyes relative to the FXS group. Shorter initial fixation on averted gaze in males with FXS was a robust predictor of the severity of their social avoidance behavior exhibited during a social greeting context, whereas parent-reported social avoidance symptoms were not related to performance in the semi-naturalistic context. This eye-tracking paradigm may represent a promising outcome measure for FXS clinical trials because it provides a quantitative index that closely maps onto core social avoidance phenotypes of FXS, can be completed in less than 20 min, and is suitable for use with individuals with low IQ.

Key Players in Key Roles: The Baystate Patient Progress Initiative to Improve Emergency Department Efficiency and Productivity.

BACKGROUND: The percentage of patients who leave the emergency department without being seen by a provider is a measure of efficiency and presents risk-management concerns. The number of patients actually "seen" by a provider is a measure of productivity. The opening of our new emergency department in December 2012, resulted in increases in both demand and the percentage of patients who left without being seen. Operational nursing leadership managed ED patient flow, but the structure was loosely organized on an ad hoc basis. METHODS: Operational nursing leadership roles were re-assigned to personnel with management aptitude and interest. The charge nurse coordinated care throughout all sections (pods) of the department while the pod lead nurse coordinated care in each pod. The flow coordinator nurse accepted transfers and emergency medical services arrivals. Nursing and physician staffing remained unchanged, and measures were calculated over a 3-year period (December 3, 2012, to December 2, 2015). The number of patients seen per day was analyzed using simple linear regression. The percentage of patients who left without being seen was analyzed using fractional logistic regression; P< 0.05 was considered statistically significant. RESULTS: The weekly mean number of patients seen per day rose 13% from 265 to 299 patients. The weekly mean percentage of patients who left without being seen declined 45% from 8.2% to 4.5%. The regression lines for both measures were significant at P < 0.001. CONCLUSION: Measures of efficiency and productivity can be improved significantly with a dedicated operational nursing leadership structure without adding nursing or physician staffing.

Cationic [(Iminophosphine)Nickel(Allyl)]+ Complexes as the First Example of Nickel Catalysts for Direct Hydroamination of Allenes.

The first example of nickel-catalyzed hydroamination of allenes is reported. The new cationic [(3-iminophosphine)nickel(allyl)]+ catalysts have been fully characterized and act regioselectively in the catalytic hydroamination of allenes with secondary amines at room temperature.

Emotion regulation and amygdala-precuneus connectivity: Focusing on attentional deployment.

Attentional deployment is an emotion regulation strategy that involves shifting attentional focus. Deploying attention to non-arousing, compared to arousing, regions of unpleasant images has been associated with reduced negative affect, reduced amygdala activation, and increased activity in fronto-parietal control networks. The current study examined neural correlates and functional connectivity associated with using attentional deployment to increase negative affect (deploying attention towards arousing unpleasant information) or to decrease negative affect (deploying attention away from arousing unpleasant information), compared to naturally viewing unpleasant images, in 42 individuals while concurrently monitoring eye movements. Directing attention to both arousing and non-arousing regions resulted in enhanced fronto-parietal activation compared to natural viewing, but only directing attention to non-arousing regions was associated with changes in amygdala activation. There were no significant differences in connectivity between naturally viewing unpleasant images and focusing on arousing regions. However, naturally viewing unpleasant images, relative to focusing on non-arousing regions, was associated with increased connectivity between the amygdala and visual cortex, while focusing on non-arousing regions of unpleasant images, compared to natural viewing, was associated with increased connectivity between the amygdala and the precuneus. Amygdala-precuneus connectivity correlated positively with eye-tracking measures of attentional deployment success and with trait reappraisal. Deploying attention away from arousing unpleasant information, then, may depend upon functional relationships between the amygdala and parietal regions implicated in attentional control. Furthermore, these relationships might relate to the ability to successfully implement attentional deployment, and the predisposition to utilize adaptive emotion regulation strategies.

The contribution of flowering time and seed content to uneven ripening initiation among fruits within Vitis vinifera L. cv. Pinot noir clusters.

MAIN CONCLUSION: Ripening initiation-associated hormonal changes and sugar accumulation for individual fruits differed by seed content and did not depend heavily on flowering time or duration from anthesis to clusters' onset of ripening. For Vitis vinifera, the ripening initiation of individual fruits in a cluster occurs unevenly. This developmental period is called véraison. Why individual fruits initiate ripening at different times is not well studied, though differences in seed content and unequal developmental durations that arise from asynchronous flowering within a cluster have been proposed. This study examined how much both variables contribute to individual fruits' ripening progress by mid-véraison, when half of berries in a cluster have initiated ripening, and whether either or both factors affect the timing of characteristic, ripening-initiation associated changes in abscisic acid and auxin before, at, and after véraison. Overall, developmental duration and flowering time did not sufficiently explain how far berries had progressed into the ripening stage because fruits did not require a fixed amount of time to initiate ripening. Fruits from early and late flowers but of similar seed content were able to initiate ripening at the same time despite differences in chronological age. This suggests either an early developmental enhancement occurred for late-initiated fruits or that flowering time is an inappropriate "day zero". Ultimately, only seed content was linked to the timing and magnitude of ripening-related hormone changes, supporting that seeds have a comparatively larger influence than flowering time on the ripening initiation of individual berries. More specifically, if the fraction of berry weight occupied by seed was high, then the initiation of ripening for that berry and its associated hormone changes were delayed relative to berries with less seed weight versus total berry weight.

Targeting androgen receptor and JunD interaction for prevention of prostate cancer progression.

BACKGROUND: Multiple studies show that reactive oxygen species (ROS) play a major role in prostate cancer (PCa) development and progression. Previously, we reported an induction of Spermidine/Spermine N(1) -Acetyl Transferase (SSAT) by androgen-activated androgen receptor (AR)-JunD protein complex that leads to over-production of ROS in PCa cells. In our current research, we identify small molecules that specifically block AR-JunD in this ROS-generating metabolic pathway. METHODS: A high throughput assay based on Gaussia Luciferase reconstitution was used to identify inhibitors of the AR-JunD interaction. Selected hits were further screened using a fluorescence polarization competitor assay to eliminate those that bind to the AR Ligand Binding Domain (LBD), in order to identify molecules that specifically target events downstream to androgen activation of AR. Eleven molecules were selected for studies on their efficacy against ROS generation and growth of cultured human PCa cells by DCFH dye-oxidation assay and DNA fluorescence assay, respectively. In situ Proximity Ligation Assay (PLA), SSAT promoter-luciferase reporter assay, and western blotting of apoptosis and cell cycle markers were used to study mechanism of action of the lead compound. RESULTS: Selected lead compound GWARJD10 with EC(50) 10 µM against ROS production was shown to block AR-JunD interaction in situ as well as block androgen-induced SSAT gene expression at IC(50) 5 µM. This compound had no effect on apoptosis markers, but reduced cyclin D1 protein level. CONCLUSIONS: Inhibitor of AR-JunD interaction, GWARJD10 shows promise for prevention of progression of PCa at an early stage of the disease by blocking growth and ROS production.

More target features in visual working memory leads to poorer search guidance: evidence from contralateral delay activity.

The visual-search literature has assumed that the top-down target representation used to guide search resides in visual working memory (VWM). We directly tested this assumption using contralateral delay activity (CDA) to estimate the VWM load imposed by the target representation. In Experiment 1, observers previewed four photorealistic objects and were cued to remember the two objects appearing to the left or right of central fixation; Experiment 2 was identical except that observers previewed two photorealistic objects and were cued to remember one. CDA was measured during a delay following preview offset but before onset of a four-object search array. One of the targets was always present, and observers were asked to make an eye movement to it and press a button. We found lower magnitude CDA on trials when the initial search saccade was directed to the target (strong guidance) compared to when it was not (weak guidance). This difference also tended to be larger shortly before search-display onset and was largely unaffected by VWM item-capacity limits or number of previews. Moreover, the difference between mean strong- and weak-guidance CDA was proportional to the increase in search time between mean strong-and weak-guidance trials (as measured by time-to-target and reaction-time difference scores). Contrary to most search models, our data suggest that trials resulting in the maintenance of more target features results in poor search guidance to a target. We interpret these counterintuitive findings as evidence for strong search guidance using a small set of highly discriminative target features that remain after pruning from a larger set of features, with the load imposed on VWM varying with this feature-consolidation process.

Dissociating temporal inhibition of return and saccadic momentum across multiple eye-movement tasks.

Saccade latencies are longer prior to an eye movement to a recently fixated location than to control locations, a phenomenon known as oculomotor inhibition of return (O-IOR). There are theoretical reasons to expect that O-IOR would vary in magnitude across different eye movement tasks, but previous studies have produced contradictory evidence. However, this may have been because previous studies have not dissociated O-IOR and a related phenomenon, saccadic momentum, which is a bias to repeat saccade programs that also influences saccade latencies. The present study dissociated the influence of O-IOR and saccadic momentum across three complex visual tasks: scene search, scene memorization, and scene aesthetic preference. O-IOR was of similar magnitude across all three tasks, while saccadic momentum was weaker in scene search.

Alpha-metalated N,N-dimethylbenzylamine rare-earth metal complexes and their catalytic applications.

This perspective summarizes our group's extensive research in the realm of organometallic lanthanide complexes, while also placing the catalytic reactions supported by these species within the context of known lanthanide catalysis worldwide, with a specific focus on phosphorus-based catalytic reactions such as intermolecular hydrophosphination and hydrophosphinylation. α-Metalated N,N-dimethylbenzylamine ligands have been utilized to generate homoleptic lanthanide complexes, which have subsequently proven to be highly active lanthanum-based catalysts. The main goal of our research program has been to enhance the catalytic efficiency of lanthanum-based complexes, which began with initial successes in the stoichiometric synthesis of organometallic lanthanide complexes and utilization of these species in catalytic hydrophosphination reactions. Not only have these species supported traditional lanthanide catalysis, such as the hydrophosphination of heterocumulenes like carbodiimides, isocyanates, and isothiocyanates, but they have also been effective for a plethora of catalytic reactions tested thus far, including the hydrophosphinylation and hydrophosphorylation of nitriles, hydrophosphination and hydrophosphinylation of alkynes and alkenes, and the heterodehydrocoupling of silanes and amines. Each of these catalytic transformations is meritorious in its own right, offering new synthetic routes to generate organic scaffolds with enhanced functionality while concurrently minimizing both waste generation and energy consumption. Objectives: We aim for the research summary presented herein to inspire and encourage other researchers to investigate f-element based stoichiometric and catalytic reactions. Our efforts in this field began with the recognition that potassium salts of benzyldimethylamine preferred deprotonation at the α-position, rather than the ortho-position, and we wondered if this regiochemistry would be retained in the formation of lanthanide complexes. The pursuit of this simple idea led first to a series of structurally fascinating homoleptic organometallic lanthanide complexes with surprisingly good stability. Fundamental studies of the protonolysis chemistry of these complexes ultimately revealed highly versatile lanthanide-based precatalysts that have propelled a catalytic investigation spanning more than a decade. We anticipate that this summative perspective will animate the synthetic as well as biological communities to consider La(DMBA)3-based catalytic methods in the synthesis of functionalized organic scaffolds as an atom-economic, convenient, and efficient methodology. Ultimately, we envision our work making a positive impact on the advancement of novel chemical transformations and contributing to progress in various fields of science and technology.

Neural correlates of attentional deployment within unpleasant pictures.

Attentional deployment is an emotion regulation strategy that involves shifting attentional focus towards or away from particular aspects of emotional stimuli. Previous studies have highlighted the prevalence of attentional deployment and demonstrated that it can have a significant impact on brain activity and behavior. However, little is known about the neural correlates of this strategy. The goal of the present studies was to examine the effect of attentional deployment on neural activity by directing attention to more or less arousing portions of unpleasant images. In Studies 1 and 2, participants passively viewed counterbalanced blocks of unpleasant images without a focus, unpleasant images with an arousing focus, unpleasant images with a non-arousing focus, neutral images without a focus, and neutral images with a non-arousing focus for 4000 ms each. In Study 2, eye-tracking data were collected on all participants during image acquisition. In both studies, affect ratings following each block indicated that participants felt significantly less negative affect after viewing unpleasant images with a non-arousing focus compared to unpleasant images with an arousing focus. In both studies, the unpleasant non-arousing focus condition compared to the unpleasant arousing focus condition was associated with increased activity in frontal and parietal regions implicated in inhibitory control and visual attention. In Study 2, the unpleasant non-arousing focus condition compared to the unpleasant arousing focus condition was associated with reduced activity in the amygdala and visual cortex. Collectively these data suggest that attending to a non-arousing portion of an unpleasant image successfully reduces subjective negative affect and recruits fronto-parietal networks implicated in inhibitory control. Moreover, when ensuring task compliance by monitoring eye movements, attentional deployment modulates amygdala activity.

Explicit and implicit category learning in categorical visual search.

Categorical search has been heavily investigated over the past decade, mostly using natural categories that leave the underlying category mental representation unknown. The categorization literature offers several theoretical accounts of category mental representations. One prominent account is that separate learning systems account for classification: an explicit learning system that relies on easily verbalized rules and an implicit learning system that relies on an associatively learned (nonverbalizable) information integration strategy. The current study assessed the contributions of these separate category learning systems in the context of categorical search using simple stimuli. Participants learned to classify sinusoidal grating stimuli according to explicit or implicit categorization strategies, followed by a categorical search task using these same stimulus categories. Computational modeling determined which participants used the appropriate classification strategy during training and search, and eye movements collected during categorical search were assessed. We found that the trained categorization strategies overwhelmingly transferred to the verification (classification response) phase of search. Implicit category learning led to faster search response and shorter target dwell times relative to explicit category learning, consistent with the notion that explicit rule classification relies on a more deliberative response strategy. Participants who transferred the correct category learning strategy to the search guidance phase produced stronger search guidance (defined as the proportion of trials on which the target was the first item fixated) with evidence of greater guidance in implicit-strategy learners. This demonstrates that both implicit and explicit categorization systems contribute to categorical search and produce dissociable patterns of data.

Assessing satisfaction of search in virtual mammograms for experienced and novice searchers.

Purpose: Satisfaction of search (SOS) is a phenomenon where searchers are more likely to miss a lesion/target after detecting a first lesion/target. Here, we investigated SOS for masses and calcifications in virtual mammograms with experienced and novice searchers to determine the extent to which: (1) SOS affects breast lesion detection, (2) similarity between lesions impacts detection, and (3) experience impacts SOS rates. Approach: The open virtual clinical trials framework was used to simulate the breast anatomy of patients, and up to two simulated masses and/or single-calcifications were inserted into the breast models. Experienced searchers (residents, fellows, and radiologists with breast imaging experience) and novice searchers (undergraduates who had no breast imaging experience) were instructed to search for up to two lesions (masses and calcifications) per image. Results: 2×2 mixed factors analysis of variances (ANOVAs) were run with: (1) single versus second lesion hit rates, (2) similar versus dissimilar second-lesion hit rates, and (3) similar versus dissimilar second-lesion response times as within-subject factors and experience as the between subject's factor. The ANOVAs demonstrated that: (1) experienced and novice searchers made a significant amount of SOS errors, (2) similarity had little impact on experienced searchers, but novice searchers were more likely to miss a dissimilar second lesion compared to when it was similar to a detected first lesion, (3) experienced and novice searchers were faster at finding similar compared to dissimilar second lesions. Conclusions: We demonstrated that SOS is a significant cause of lesion misses in virtual mammograms and that reader experience impacts detection rates for similar compared to dissimilar abnormalities. These results suggest that experience may impact strategy and/or recognition with theoretical implications for determining why SOS occurs.

Are all real-world objects created equal? Estimating the "set-size" of the search target in visual working memory.

Are all real-world objects created equal? Visual search difficulty increases with the number of targets and as target-related visual working memory (VWM) load increases. Our goal was to investigate the load imposed by individual real-world objects held in VWM in the context of search. Measures of visual clutter attempt to quantify real-world set-size in the context of scenes. We applied one of these measures, the number of proto-objects, to individual real-world objects and used contralateral delay activity (CDA) to measure the resulting VWM load. The current study presented a real-world object as a target cue, followed by a delay where CDA was measured. This was followed by a four-object search array. We compared CDA and later search performance from target cues containing a high or low number of proto-objects. High proto-object target cues resulted in greater CDA, longer search RTs, target dwell times, and reduced search guidance, relative to low proto-object targets. These findings demonstrate that targets with more proto-objects result in a higher VWM load and reduced search performance. This shows that the number of proto-objects contained within individual objects produce set-size like effects in VWM and suggests proto-objects may be a viable unit of measure of real-world VWM load. Importantly, this demonstrates that not all real-world objects are created equal.

Negative cues minimize visual search specificity effects.

Prior target knowledge (i.e., positive cues) improves visual search performance. However, there is considerable debate about whether distractor knowledge (i.e., negative cues) can guide search. Some studies suggest the active suppression of negatively cued search items, while others suggest the initial capture of attention by negatively cued items. Prior work has used pictorial or specific text cues but has not explicitly compared them. We build on that work by comparing positive and negative cues presented pictorially and as categorical text labels using photorealistic objects and eye movement measures. Search displays contained a target (cued on positive trials), a lure from the target category (cued on negative trials), and four categorically-unrelated distractors. Search performance with positive cues resulted in stronger attentional guidance and faster object recognition for pictorial relative to categorical cues (i.e., a pictorial advantage, suggesting specific visual details afforded by pictorial cues improved search). However, in most search performance metrics, negative cues mitigate the pictorial advantage. Given that the negatively cued items captured attention, generated target guidance but mitigated the pictorial advantage, these results are partly consistent with both existing theories. Specific visual details provided in positive cues produce a large pictorial advantage in all measures, whereas specific visual details in negative cues only produce a small pictorial advantage for object recognition but not for attentional guidance. This asymmetry in the pictorial advantage suggests that the down-weighting of specific negatively cued visual features is less efficient than the up-weighting of specific positively cued visual features.

The Effect of Asparagus Extract on Pancreatic Cancer: An Intriguing Surprise.

BACKGROUND: Pancreatic cancer is the most lethal digestive cancer and the fourth overall cause of cancer death in the US. Asparagus, a widely consumed savory vegetable, is a rich source of antioxidants, saponins, vitamins, and minerals. In recent years, it has been shown that components of asparagus have anticancer effects on endometrial adenocarcinoma, and in prostate, breast, and colon cancer. In pancreatic cancer, it has been shown to have an anticancer effect on the KLM1-R cell line. This study was designed to investigate if asparagus extract (AE) had any effect on the growth of a widely used pancreatic cancer cell line MDAPanc-28 and to elucidate possible molecular mechanisms behind it. MATERIALS AND METHODS: Clonogenic survival assay, proliferation, and caspase-3 activity kits were used to evaluate the effects of AE on cell survival, proliferation, and apoptosis pathway of MDAPanc-28 cells. We further investigated the possible molecular mechanisms by using reverse transcription-polymerase chain reaction. RESULTS: The colony numbers and proliferation of MDAPanc-28 cells were surprisingly increased when treated with AE. The relative caspase-3 activity in cancer cells decreased when they were treated with AE. The pro-proliferative effect of AE on MDAPanc-28 cells correlated with down-regulation of anti-proliferative molecules P21 and P53. The potential anti-apoptotic effect of AE correlated with down-regulation of the pro-apoptotic molecule Fas cell surface death receptor (FAS) and down-regulation of caspase-3 activity. CONCLUSION: AE exhibits a pro-tumor effect on MDAPanc-28 pancreatic cancer cells by down-regulation of P21, P53, and FAS.

From "satisfaction of search" to "subsequent search misses": a review of multiple-target search errors across radiology and cognitive science.

For over 50 years, the satisfaction of search effect has been studied within the field of radiology. Defined as a decrease in detection rates for a subsequent target when an initial target is found within the image, these multiple target errors are known to underlie errors of omission (e.g., a radiologist is more likely to miss an abnormality if another abnormality is identified). More recently, they have also been found to underlie lab-based search errors in cognitive science experiments (e.g., an observer is more likely to miss a target 'T' if a different target 'T' was detected). This phenomenon was renamed the subsequent search miss (SSM) effect in cognitive science. Here we review the SSM literature in both radiology and cognitive science and discuss: (1) the current SSM theories (i.e., satisfaction, perceptual set, and resource depletion theories), (2) the eye movement errors that underlie the SSM effect, (3) the existing efforts tested to alleviate SSM errors, and (4) the evolution of methodologies and analyses used when calculating the SSM effect. Finally, we present the attentional template theory, a novel mechanistic explanation for SSM errors, which ties together our current understanding of SSM errors and the attentional template literature.

Decoding Brain Representations by Multimodal Learning of Neural Activity and Visual Features.

This work presents a novel method of exploring human brain-visual representations, with a view towards replicating these processes in machines. The core idea is to learn plausible computational and biological representations by correlating human neural activity and natural images. Thus, we first propose a model, EEG-ChannelNet, to learn a brain manifold for EEG classification. After verifying that visual information can be extracted from EEG data, we introduce a multimodal approach that uses deep image and EEG encoders, trained in a siamese configuration, for learning a joint manifold that maximizes a compatibility measure between visual features and brain representations. We then carry out image classification and saliency detection on the learned manifold. Performance analyses show that our approach satisfactorily decodes visual information from neural signals. This, in turn, can be used to effectively supervise the training of deep learning models, as demonstrated by the high performance of image classification and saliency detection on out-of-training classes. The obtained results show that the learned brain-visual features lead to improved performance and simultaneously bring deep models more in line with cognitive neuroscience work related to visual perception and attention.