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Cell growth rate is regulated in response to the abundance and molecular form of essential nutrients. In Saccharomyces cerevisiae (budding yeast), the molecular form of environmental nitrogen is a major determinant of cell growth rate, supporting growth rates that vary at least threefold. Transcriptional control of nitrogen use is mediated in large part by nitrogen catabolite repression (NCR), which results in the repression of specific transcripts in the presence of a preferred nitrogen source that supports a fast growth rate, such as glutamine, that are otherwise expressed in the presence of a nonpreferred nitrogen source, such as proline, which supports a slower growth rate. Differential expression of the NCR regulon and additional nitrogen-responsive genes results in >500 transcripts that are differentially expressed in cells growing in the presence of different nitrogen sources in batch cultures. Here we find that in growth rate–controlled cultures using nitrogen-limited chemostats, gene expression programs are strikingly similar regardless of nitrogen source. NCR expression is derepressed in all nitrogen-limiting chemostat conditions regardless of nitrogen source, and in these conditions, only 34 transcripts exhibit nitrogen source–specific differential gene expression. Addition of either the preferred nitrogen source, glutamine, or the nonpreferred nitrogen source, proline, to cells growing in nitrogen-limited chemostats results in rapid, dose-dependent repression of the NCR regulon. Using a novel means of computational normalization to compare global gene expression programs in steady-state and dynamic conditions, we find evidence that the addition of nitrogen to nitrogen-limited cells results in the transient overproduction of transcripts required for protein translation. Simultaneously, we find that that accelerated mRNA degradation underlies the rapid clearing of a subset of transcripts, which is most pronounced for the highly expressed NCR-regulated permease genes GAP1, MEP2, DAL5, PUT4, and DIP5. Our results reveal novel aspects of nitrogen-regulated gene expression and highlight the need for a quantitative approach to study how the cell coordinates protein translation and nitrogen assimilation to optimize cell growth in different environments.

Rett syndrome is a neurodevelopmental disorder characterized by cognitive and adaptive regression with autistic features, loss of acquired skills, and stereotypic hand movements that almost exclusively affects females. It is an X-linked dominant disorder, with presumed lethality in males. Nonetheless, there are a few descriptions of males suspected of having Rett syndrome. With the recent discovery that the MECP2 gene is responsible for most cases of Rett syndrome, it is possible to molecularly assess cases of affected males by direct sequencing analysis. We describe an Israeli family consisting of a female having classic Rett syndrome and a male sibling with severe neonatal encephalopathy. Molecular analysis revealed that both sister and brother have the same MECP2 gene mutation; however, their mother does not. This case, as well as other published studies of males with MECP2 mutations, reveals that the clinical manifestations in viable males vary from neonates with severe encephalopathy to adults with mental retardation and demonstrate genotype-phenotype correlations. (J Child Neurol 2002;17:20–24). [ABSTRACT FROM AUTHOR]

Introduction: Individuals with subjective cognitive decline (SCD) express concern about self-perceived cognitive decline despite no objective impairment and are at higher risk of developing Alzheimer's disease. Despite documented links between SCD and repetitive negative thinking (RNT), the specific impact of RNT on brain integrity and cognition in exacerbating the SCD condition remains unclear. We aimed to investigate the influence of RNT on global cognition and brain integrity, and their interrelationships among healthy middle-aged and older adults experiencing SCD. Methods: Out of 616 individuals with neuroimaging and neuropsychological data available, 89 (mean age = 56.18 years; 68.54% females) met SCD criteria. Eighty-nine non-SCD individuals matched by age, sex, and education were also selected and represented the control group (mean age = 56.09 years; 68.54% females). Global cognition was measured using the preclinical Alzheimer's cognitive composite (PACC5), which includes dementia screening, episodic memory, processing speed, and category fluency tests. RNT was calculated through three questionnaires assessing intrusive thoughts, persistent worry, and rumination. We generated cortical thickness (CTh) maps and quantified the volume of white matter lesions (WML) in the whole brain, as grey and white matter integrity measures, respectively. Results: SCD individuals exhibited higher RNT scores, and thinner right temporal cortex compared to controls. No differences were observed in PACC5 and WML burden between groups. Only the SCD group demonstrated positive associations in the CTh-PACC5, CTh-RNT, and WML-RNT relationships. Discussion: In this cross-sectional study, RNT was exclusively associated with brain integrity in SCD. Even though our findings align with the broader importance of investigating treatable psychological factors in SCD, further research may reveal a modulatory effect of RNT on the relationship between cognition and brain integrity in SCD. [ABSTRACT FROM AUTHOR]

Homocysteine (Hcy) is a cardiovascular risk factor implicated in cognitive impairment and cerebrovascular disease but has also been associated with Alzheimer's disease. In 160 healthy older adults (mean age = 69.66 ± 9.95 years), we sought to investigate the association of cortical brain volume with white matter hyperintensity (WMH) burden and a previously identified Hcy-related multivariate network pattern showing reductions in subcortical gray matter (SGM) volumes of hippocampus and nucleus accumbens with relative preservation of basal ganglia. We additionally evaluated the potential role of these brain imaging markers as a series of mediators in a vascular brain pathway leading to age-related cognitive dysfunction in healthy aging. We found reductions in parietal lobar gray matter associated with the Hcy-SGM pattern, which was further associated with WMH burden. Mediation analyses revealed that slowed processing speed related to aging, but not executive functioning or memory, was mediated sequentially through increased WMH lesion volume, greater Hcy-SGM pattern expression, and then smaller parietal lobe volume. Together, these findings suggest that volume reductions in parietal gray matter associated with a pattern of Hcy-related SGM volume differences may be indicative of slowed processing speed in cognitive aging, potentially linking cardiovascular risk to an important aspect of cognitive dysfunction in healthy aging. [ABSTRACT FROM AUTHOR]

Background: Visuospatial memory impairment is a common symptom of Alzheimer’s disease; however, conventional visuospatial memory tests are insufficient to fully reflect visuospatial memory impairment in daily life. Methods: To address patients’ difficulties in locating and recalling misplaced objects, we introduced a novel visuospatial memory test, the Hidden Objects Test (HOT), conducted in a virtual environment. We categorized HOT scores into prospective memory, item free-recall, place free-recall, item recognition, and place-item matching scores. To validate the VR memory test, we compared HOT scores among individuals with Alzheimer’s disease (AD), amnestic mild cognitive impairment (aMCI), and normal controls (NC), and also compared these scores with those of conventional neuropsychological tests. We tracked the participants’ movement paths in the virtual environment and assessed basic features, such as total distance, duration, and speed. Additionally, we performed walking trajectory pattern mining such as outlier and stay-point detection. Results: We designed and implemented the HOT to simulate a house’s living room and assess participants’ ability to locate hidden objects. Our preliminary results showed that the total HOT score differed among 17 patients with AD, 14 with aMCI, and 15 NC (p  <  0.001). The total HOT score correlated positively with conventional memory test scores (p  <  0.001). Walking trajectories showed that patients with AD and aMCI wandered rather than going straight to the hidden objects. In terms of basic features, the total duration was significantly greater in AD than in NC (p  =  0.008). In terms of trajectory pattern mining, the number of outliers, which were over 95% of the estimated trajectory, was significantly higher in AD than in NC (p  =  0.002). The number of stay points, an index in which participants stayed in the same position for more than 2  s, was significantly higher in patients with AD and aMCI compared with NC (AD vs. NC: p  =  0.003, aMCI vs. NC: p  =  0.019). Conclusion: The HOT simulating real life showed potential as an ecologically valid test for assessing visuospatial memory function in daily life. Walking trajectory analysis suggested that patients with AD and aMCI wandered rather than going straight toward the hidden objects. [ABSTRACT FROM AUTHOR]

Introduction: Social isolation is one of the strongest predictors of increased risk of mortality in older adulthood. The ability to form and maintain the social relationships that mitigate this risk is partially regulated by the oxytocinergic system and one's ability to attend to and process social information. We have previously shown that an epigenetic change to the DNA of the oxytocin receptor gene (OXTR methylation) affects the salience of social information in young adults. Little is known about how the oxytocinergic system ages and what effect this aging system has on social cognitive abilities throughout the lifespan. Methods: Here we explored age-related differences in the association between neural response during selective social attention and OXTR DNA methylation in young (age 18--31) and older (age 58-81) adults. Participants underwent fMRI during a selective social attention task and provided a DNA sample for the assessment of OXTR methylation. Results and Discussion: We found that older adults activated diffuse areas of visual cortex and dorsolateral prefrontal cortex during selective social attention, consistent with the dedifferentiation and compensatory neural activation commonly reported in aging. We found a significant age-by-OXTR methylation interaction on neural response when attending to social stimuli in a complex display; young adults displayed a positive association between OXTR methylation and neural activation, replicating our prior finding that young adults with presumed diminished endogenous access to oxytocin recruit regions of the attentional cortex to a greater extent. This association did not hold for older adults. Instead, perceived social support interacted with OXTR methylation to influence neural response during selective social attention. These data suggest that environmental factors like social support moderate biological processes in aging and highlight the importance of a lifespan perspective for understanding associations between individual differences in the oxytocinergic system, neural function, and social behavior. [ABSTRACT FROM AUTHOR]

Objective: Digital cognitive assessments (DCAs) provide insight into cognition and behavior that remains inaccessible through standard assessment approaches. However, the availability of DCAs and the requisite toolkits to extract and analyze meaningful features from these datasets are largely constrained to technical specialists or through fee-for-service commercial entities. The NKI- Rockland Sample provides a large- scale lifespan data sample featuring DCAs, and also openly shares its DCA tasks through the open-source MindLogger platform along with pipelines for feature extraction and analyses. Here we present normative performance from a digital version of Archimedes Spiral Drawing. Participants and Methods: NKI-RS2 participants were largely drawn from the existing NKI-RS participant pool (n= 1,500), aged 885. The NKI-RS2 is in year 1 of data collection; here, we report on a subset of participants (n= 9) who performed a digitized version of the Archimedes Spiral Drawing task. This graphomotor task with well-established research and clinical utility in movement disordered populations was adapted for use for off-the-shelf tablet devices. The NKI-RS2 implements these tasks on an Apple iPad Pro2, sampling participant drawing at 120Hz, and featuring pixel- and millisecond- level resolution for all tasks. On the Spiral Drawing and Recall Tests participants traced five Archimedes spirals from the center outward through four windings presented on the iPad. They were then asked to replicate the spiral freehand three times. From these spiral drawings, we extracted time to completion, distance covered, speed/ speed variability, rotational smoothness, number of crossings, mean absolute error, bias, and goodness of fit to the ideal Archimedes spiral. Results: Comparing the tracing and recall conditions, participants showed significantly faster drawing speed (t[8]=5.32, p<.001), more variable drawing speed (t[8]=5.93, p<.001), reduced goodness of fit to the template t[8]=4.99, p<.002, and reduced rotational smoothness (t[8]=7.43, p<.0003) in the recall conditions. Collapsing across conditions, age predicted more variable drawing speed: t[8]= 2.77 p<.019, greater tracing error (t[8] = 2.69, p<.0227), and reduced rotational smoothness (t[8] = 2.67, p<.024). Between conditions, age predicts a greater increase in drawing speed variability (t[8] = 9.76, p<.0006). Conclusions: Using the open source MindLogger platform and off-the-shelf digital tablets, we were able to replicate classic paper and pen neuropsychological tests. By adapting these tasks to DCA, we were able to extract meaningful features that are not otherwise accessible (drawing speed, variability, etc.), or that would require additional hardware solutions (e.g., dwell time). By making these tasks and their processing pipelines available, the NKI-RS2 can facilitate the democratization of DCA and DCA analysis to a broader range of researchers and clinicians. [ABSTRACT FROM AUTHOR]

Objective: Digitized cognitive assessment captures rich behavioral information that remains unmeasured using conventional methods. Data capture tools recently accessible only in specialized laboratories are now feasible at scale using off-the-shelf tablet devices. This study aims to share data from a digitized cognitive assessment embedded in an open-science research program collecting extensive neuroimaging, health, behavioral, neuropsychological, and psychiatric characterizations to advance translational cognitive neuroscience. In this research we present normative performance metrics from a digital version of the Trail Making Test. Participants and Methods: The NKI-Rockland Sample (NKI-RS) has provided a model for openly-shared lifespan normative neuroimaging resources contributed by a community-ascertained sample (n=1,500, aged 6-85) and generating over 400 publications across diverse research areas. The next generation NKI-RS study (recruitment target= 600, aged 9-75) aims to enrich these resources for brain-behavioral research, normative reference, and biomarker discovery. One focus of innovation is the inclusion of digitized cognitive assessments (DCAs) utilizing an open-resource task development and data collection platform (Mindlogger, Child Mind Institute). We present preliminary data from a digitized version of the Trail Making Tests and report early descriptive metrics. The TMTs was administered via an iPad Pro using an Apple pen as part of a laboratory-based EEG procedure. The TMTs follows standard administration instructions, including a practice sample before each test condition. Error feedback is included in the task implementation such that an incorrect connection is marked with an "x" and the participant is directed to the last correct circle to continue. Feedback is automated within the task. Pixel-level spatial resolution and millisecond timing is captured across all drawing tasks. Task design, implementation, and preliminary performance metrics including speed, accuracy, and variability are reported. Results: Preliminary data include 12 participants from the NKI-RS2 study ranging in age from 11-75 years (M= 52.83, SD= 19.97); 67% female. Overall participants took longer to complete condition B (Mb = 51.71 secs) compared to condition A (Ma = 23.07 secs), p= 0.0005. Connections were made more slowly (Ma = 37.47 secs vs. Mb = 24.50 secs, p< 0.001) and connection speed was more variable (CVa = 0.90 vs. CVb = 1.22, p< 0.01) on condition B versus A. Connection speed decreased and speed variability increased with age (t[11 ]= -3.25, p= 0.05, t[11]= -3.63, p< 0.01, respectively). Time spent within circles (dwell time) was significantly greater in B versus A (t[11]= 6.81, p< 0.001). Number of errors were limited (MA =.89 and MB = 1.0, range 0-2 in both tests) with no difference between tests or effects of age (both ps >0.05). Conclusions: These preliminary data from the NKI-RS2 normative neuroimaging study demonstrate that a digitized version of a classic neuropsychological test is feasible across a diverse range of community participants, and replicates known age effects. The advantages of growing access to these DCA tools and the shared data resources they will produce has the potential to revolutionize neuropsychological research and clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Performance validity tests (PVTs) provide a methodological approach to detecting credible neurocognitive performances. This proves invaluable to the diagnostic process, as it allows neuropsychologists to objectively determine if an evaluation reflects a patient's true neurocognitive abilities or if external factors are impacting the results. However, their addition to a testing battery can increase an already lengthy evaluation. As such, there is a need for sensitive but less time intensive PVTs. The purpose of this study is to validate the Coin-in-Hand (CIH) procedure as a quick and effective PVT within a veteran population. Participants and Methods: 68 English-speaking patients were identified from an outpatient neuropsychological assessment dataset. Performances were correlated to the well- validated Reliable Digit Span (RDS), and several other soft indicators of task engagement including expanded COWAT, BVMT-False Alarms (FA), WCST Failure to Maintain Set (FTM), TOMM, and the RBANS Effort Index (EI). All participants attempted CIH and RDS, testing was discontinued if 2 or more PVTs were invalid. An AUC analysis was conducted to determine how well the CIH discriminated between valid and invalid performance and determine the tests optimal cut-off score (sensitivity > 0.90 while maintaining the highest possible specificity). Logistic Regression was conducted to determine how well the CIH predicted performance validity. Results: Subject mean(SD) age and education were 55.25 (16.06) and 13.41 (2.55) years, respectively. 17% female, 60% Caucasian, and 32% Black. Descriptive statistics for each of the other performance validity tests were gathered. The CIH demonstrated low diagnostic accuracy (AUC =.66; p >.05; CI =.51 -.81); a cut score of <8 resulted in a sensitivity of.96 and a specificty of.64. Logistic Regression showed that CIH performance significantly predicted performance validity (X2 = -0.93; df = 1; N = 68; p <.05), accounting for 18-28% of the variance in performance classification (Cox & Snell R2 =.18; Nagelkerke R2 =.28). It correctly classified 96% of valid performers, but only correctly classified 35% of invalid performers, with an overall correct prediction rate of 83%. A predicted chase in log odds (B= -.93) and odd ratio [Exp (B) =.40] indicated that every unit increase in CIH score was associated with a decrease probability of performance invalidity. Logistic regression was also used to calculate the probability of performance invalidity at each possible CIH score (Table 1). Conclusions: Results suggests that poor performance on CIH does not necessarily equate to invalid performances, but instead, should act as a screener to cue neuropsychologists working with Veterans that additional PVTs should be considered. Overall, it was determined that CIH was able to correctly predict 35% of invalid performers and 96% of valid performers, with an overall correct prediction rate of 83%, suggesting the procedure may be too simple to be an effective standalone PVT for clinical use. These results also highlight that every correct response on the CIH was associated with a decreased probability of performance invalidity. Additionally, an AUC analysis determined the tests optimal cut off score to be <8, suggesting that shortening the procedure may be as effective as giving the full 10 trials. [ABSTRACT FROM AUTHOR]

Neuropsychological test scores tap a number of underlying cognitive abilities. Examining the means by which omnibus scores are achieved provides considerable information regarding brain - behavior relationships and a richer context for clinical interpretation. This examination is the core tenant of the Boston Process Approach. Nonetheless, quantification of errors and process can be time consuming. However, the development of digital assessment technology is able to meet this challenge. For example, using a digital clock drawing test, previously unappreciated behaviors are now easily quantified and can dissociate between dementia and MCI subtypes. Research presented in this paper session provides additional insight into how digital technology can be leveraged as a powerful tool to capture behavior that, until recently, was either impractical or impossible to measure. The assessment of graphomotor behavior can be challenging. In the context of a large-scale normative neuroimaging study, Colcombe and colleagues have engineered a digital Archimedes Spiral Test that includes measures of speed variability, rotational smoothness, and goodness of fit to the model. The temporal and spatial precision of these metrics is impressive. This research shows that, age predicted greater variable drawing speed, greater tracing errors, reduced rotational smoothness, and increasing drawing speed variability. MacKay-Brandt and colleagues present data using a digital version of the Trail Making Tests (TMT), one of the most commonly administered neuropsychological tests. This research provides a panel of new parameters to evaluate TMT performance, including detailed speed metrics with spatial segregation to parse circle connection time from dwell time within a circle. Interestingly, dwell time, rather than traditional total time to completion, was the strongest predictor of differences between conditions and across age. Baliga and colleagues present data on a protocol of novel cancellation tests. Memory clinic patients were classified into groups presenting with mild dementia, mild cognitive impairment, and those who were cognitively normal. Digital parameters of interest included correct responses, commissions, mean intra-response latency, and mean apple pencil touch. Using these parameters, significant between group differences were obtained. Moreover, logistic regression analyses were able to classify patients into their respective groups. It is well understood that paragraph recall tests assess a variety of underlying cognitive abilities. Andersen and colleagues studied Logical Memory recall in the Long-Life Family Study and extracted linguistic parameters that included word count, grammatical features (e.g., prepositions), and content words related to specific categories (e.g., work). Participants were classified as cognitively normal or impaired. Analyses identified distinct linguistic features of free recall that predicted cognitive status. Hershkovich and colleagues extract measured pauses and speech frequency behavior also from a paragraph recall test. A combination of paragraph recall pause duration, speech frequency parameters, and demographic variables were able to classify older adults with and without cognitive compromise. Collectively, the evidence provided in this series of papers demonstrates that digital platforms can capture and quantify highly nuanced neurocognitive behavior to enrich information available to researchers and clinicians for analysis and clinical formulations. Digital assessment technology holds promise to realize the vision of the Boston Process Approach and revolutionize neuropsychological assessment. [ABSTRACT FROM AUTHOR]

To extend the use of card technology to highervalue transactions, card issuers now offer a range of 'electronic accounts payable' (EAP) products, often referred to as 'virtual cards.' In general, EAP is a non-plastic purchasing-card (p-card) account that is used to pay for goods and services after an invoice has been received. A t that time, EAP card number information is transmitted or referenced for payment. The key feature of EAP is the dynamically adjustable line of credit supporting the account. Hence, the available credit on a card account is adjusted to match a specific transaction to be charged. After the transaction is completed, the available line of credit on the card is of little or no value. A wide variety of anecdotal commentary exists about the benefits of EAP, but facts about its use are limited. The purpose of this paper is to provide the reader with results from a recent survey about EAP use in North America. Specifically, the results show the types of EAP being used in North America, EAP spending norms, the benefits reported from EAP use, past and expected future growth of EAP spending, and the role of supplier acceptance to the success of EAP. [ABSTRACT FROM AUTHOR]