Association of Intrinsic Functional Connectivity between the Locus Coeruleus and Salience Network with Attentional Ability.

The locus coeruleus (LC) is a brainstem region associated with broad neural arousal because of norepinephrine production, but it has increasingly been associated with specific cognitive processes. These include sustained attention, with deficits associated with various neuropsychological disorders. Neural models of attention deficits have focused on interrupted dynamics between the salience network (SAL) with the frontoparietal network, which has been associated with task-switching and processing of external stimuli, respectively. Conflicting findings for these regions suggest the possibility of upstream signaling leading to attention dysfunction, and recent research suggests LC involvement. In this study, resting-state functional connectivity and behavioral performance on an attention task was examined within 584 individuals. Analysis revealed significant clusters connected to LC activity in the SAL. Given previous findings that attention deficits may be caused by SAL network switching dysfunctions, findings here further suggest that dysfunction in LC-SAL connectivity may impair attention.

Chloride Ligands on DNA-Stabilized Silver Nanoclusters.

DNA-stabilized silver nanoclusters (AgN-DNAs) are known to have one or two DNA oligomer ligands per nanocluster. Here, we present the first evidence that AgN-DNA species can possess additional chloride ligands that lead to increased stability in biologically relevant concentrations of chloride. Mass spectrometry of five chromatographically isolated near-infrared (NIR)-emissive AgN-DNA species with previously reported X-ray crystal structures determines their molecular formulas to be (DNA)2[Ag16Cl2]8+. Chloride ligands can be exchanged for bromides, which red-shift the optical spectra of these emitters. Density functional theory (DFT) calculations of the 6-electron nanocluster show that the two newly identified chloride ligands were previously assigned as low-occupancy silvers by X-ray crystallography. DFT also confirms the stability of chloride in the crystallographic structure, yields qualitative agreement between computed and measured UV-vis absorption spectra, and provides interpretation of the 35Cl-nuclear magnetic resonance spectrum of (DNA)2[Ag16Cl2]8+. A reanalysis of the X-ray crystal structure confirms that the two previously assigned low-occupancy silvers are, in fact, chlorides, yielding (DNA)2[Ag16Cl2]8+. Using the unusual stability of (DNA)2[Ag16Cl2]8+ in biologically relevant saline solutions as a possible indicator of other chloride-containing AgN-DNAs, we identified an additional AgN-DNA with a chloride ligand by high-throughput screening. Inclusion of chlorides on AgN-DNAs presents a promising new route to expand the diversity of AgN-DNA structure-property relationships and to imbue these emitters with favorable stability for biophotonics applications.

Source of perceived social support and cognitive change: an 8-year prospective cohort study.

OBJECTIVES: This study explored the longitudinal association between overall and individual sources of social support and global cognitive function in older adults.Methods:Data were drawn from three waves (2006, 2010 and 2014) of the Health and Retirement Study (HRS). The analytic sample included participants aged 65 and above who were married and had at least one child (N = 1319). Global cognitive function was measured through a 35-point Telephone Interview Cognitive Screen (TICS). Perceived social support was measured via questions across four sources of support (spouse, child, other family members, and friends). Analyses were conducted using Hierarchical Linear Modeling (HLM) with the addition of a cross-lagged panel model (CLPM). RESULTS: There was no significant association between perceived overall social support and global cognitive function over time (ß=-0.02, p=0.19). However, changes in perceived support from children were positively associated with changes in global cognition (ß=0.05,p<0.01). In contrast, changes in perceived support from other family members were negatively associated with changes in cognitive function (ß=-0.07,p<0.01). CONCLUSIONS: Our findings highlight the importance of examining perceived social support from specific elements of one's social networks, rather than in an aggregated variable. Although the positive effect of perceived support from children may be small to moderate, the findings could provide a target for interventions to protect the cognitive function of older adults.

A Disulfide-Stabilized Aß that Forms Dimers but Does Not Form Fibrils.

Aß dimers are a basic building block of many larger Aß oligomers and are among the most neurotoxic and pathologically relevant species in Alzheimer's disease. Homogeneous Aß dimers are difficult to prepare, characterize, and study because Aß forms heterogeneous mixtures of oligomers that vary in size and can rapidly aggregate into more stable fibrils. This paper introduces AßC18C33 as a disulfide-stabilized analogue of Aß42 that forms stable homogeneous dimers in lipid environments but does not aggregate to form insoluble fibrils. The AßC18C33 peptide is readily expressed in Escherichia coli and purified by reverse-phase HPLC to give ca. 8 mg of pure peptide per liter of bacterial culture. SDS-PAGE establishes that AßC18C33 forms homogeneous dimers in the membrane-like environment of SDS and that conformational stabilization of the peptide with a disulfide bond prevents the formation of heterogeneous mixtures of oligomers. Mass spectrometric (MS) studies in the presence of dodecyl maltoside (DDM) further confirm the formation of stable noncovalent dimers. Circular dichroism (CD) spectroscopy establishes that AßC18C33 adopts a ß-sheet conformation in detergent solutions and supports a model in which the intramolecular disulfide bond induces ß-hairpin folding and dimer formation in lipid environments. Thioflavin T (ThT) fluorescence assays and transmission electron microscopy (TEM) studies indicate that AßC18C33 does not undergo fibril formation in aqueous buffer solutions and demonstrate that the intramolecular disulfide bond prevents fibril formation. The recently published NMR structure of an Aß42 tetramer (PDB: 6RHY) provides a working model for the AßC18C33 dimer, in which two ß-hairpins assemble through hydrogen bonding to form a four-stranded antiparallel ß-sheet. It is anticipated that AßC18C33 will serve as a stable, nonfibrilizing, and noncovalent Aß dimer model for amyloid and Alzheimer's disease research.

CowN sustains nitrogenase turnover in the presence of the inhibitor carbon monoxide.

Nitrogenase is the only enzyme capable of catalyzing nitrogen fixation, the reduction of dinitrogen gas (N2) to ammonia (NH3). Nitrogenase is tightly inhibited by the environmental gas carbon monoxide (CO). Nitrogen-fixing bacteria rely on the protein CowN to grow in the presence of CO. However, the mechanism by which CowN operates is unknown. Here, we present the biochemical characterization of CowN and examine how CowN protects nitrogenase from CO. We determine that CowN interacts directly with nitrogenase and that CowN protection observes hyperbolic kinetics with respect to CowN concentration. At a CO concentration of 0.001 atm, CowN restores nearly full nitrogenase activity. Our results further indicate that CowN's protection mechanism involves decreasing the binding affinity of CO to nitrogenase's active site approximately tenfold without interrupting substrate turnover. Taken together, our work suggests CowN is an important auxiliary protein in nitrogen fixation that engenders CO tolerance to nitrogenase.

Shape Entropy of a Reconfigurable Ising Surface.

Disclinations in a 2D sheet create regions of Gaussian curvature whose inversion produces a reconfigurable surface with many distinct metastable shapes, as shown by molecular dynamics of a disclinated graphene monolayer. This material has a near-Gaussian "density of shapes" and an effectively antiferromagnetic interaction between adjacent cones. A∼10 nm patch has hundreds of distinct metastable shapes with tunable stability and topography on the size scale of biomolecules. As every conical disclination provides an Ising-like degree of freedom, we call this technique "Isigami."

KCNQ5 activation is a unifying molecular mechanism shared by genetically and culturally diverse botanical hypotensive folk medicines.

Botanical folk medicines have been used throughout human history to treat common disorders such as hypertension, often with unknown underlying mechanisms. Here, we discovered that hypotensive folk medicines from a genetically diverse range of plant species each selectively activated the vascular-expressed KCNQ5 potassium channel, a feature lacking in the modern synthetic pharmacopeia, whereas nonhypotensive plant extracts did not. Analyzing constituents of the hypotensive Sophora flavescens root, we found that the quinolizidine alkaloid aloperine is a KCNQ-dependent vasorelaxant that potently and isoform-selectively activates KCNQ5 by binding near the foot of the channel voltage sensor. Our findings reveal that KCNQ5-selective activation is a defining molecular mechanistic signature of genetically diverse traditional botanical hypotensives, transcending plant genus and human cultural boundaries. Discovery of botanical KCNQ5-selective potassium channel openers may enable future targeted therapies for diseases including hypertension and KCNQ5 loss-of-function encephalopathy.

Increasing the Flexibility of Implicit Personality Assessment: An Examination of a Universal Assessment Procedure of the Self.

The current studies systematically examined a new version of the Questionnaire-Based Implicit Association Test (qIAT), which minimizes the differences between direct and indirect modes of assessment. Studies 1a (N = 276) and 1 b (N = 238) tested a method that enables an indirect assessment of questionnaires that include only non-reversed items. Studies 2a (N = 255) and 2 b (N = 284) tested a task that substitutes the problematic construct-related category labels with generic, universal categories. These studies, which focused on extraversion, supported the feasibility, reliability and validity of this procedure. Studies 3a-3c (N = 159, 154 and 151, respectively) supported the internal consistency, test-retest reliability and convergent validity of these methods, assessing three well-researched, semantically complex personality scales: Aggressive Humor Style, Need for Closure and Anxiety Sensitivity. Studies 4a (N = 195) and 4 b (N = 283) supported the implicitness of the qIAT, as most respondents were not aware of this task's purpose. In Study 4c (N = 598), participants who reported using antidepressants had lower self-esteem qIAT scores compared to a control group, thus supporting the criterion validity of this task. Taken together, findings suggest that the new qIAT substantially increases the scope of indirect personality assessment.

Disparities in COVID-19 Mortality Rates: Implications for Rural Health Policy and Preparedness.

CONTEXT: It is well established that rural communities face geographic and socioeconomic challenges linked to higher rates of health disparities across the United States, though the coronavirus disease 2019 (COVID-19) impact on rural communities is less certain. OBJECTIVE: To understand the COVID-19 pandemic's impact on rural communities in Tennessee, investigate differences in rural-urban mortality rates after controlling for confounding variables, and inform state pandemic response policy. DESIGN: A cross-sectional analysis of cumulative COVID-19 morality rates. SETTING/PARTICIPANTS: Tennessee county-level COVID-19 mortality data from March 1, 2020, to January 31, 2021, were matched with county-level sociodemographic and health data from public datasets: Agency for Healthcare Research and Quality Social Determinants of Health, PLACES: Local Data for Better Health County Data, and the US Census Bureau. County status was defined using the 2013 National Center for Health Statistics Urban-Rural Classification. MAIN OUTCOME MEASURES: A negative binomial regression model estimated adjusted incidence rate ratio and 95% confidence intervals (CI) for rural compared with urban mortality. Unadjusted rate ratios and rate differences for COVID-19 mortality in rural versus urban counties were compared with those for influenza and pneumonia and all-cause mortality over the past 5 years. RESULTS: During the study period, 9650 COVID-19 deaths occurred across 42 urban and 53 rural counties. Controlling for county-level sociodemographic characteristics, health care access, and comorbidities, incidence rate ratio was 1.13 (95% CI, 1.00-1.28, P < .05) for rural as compared with urban deaths. Unadjusted COVID-19 mortality risk difference between rural and urban counties was greater (61.85, 95% CI, 54.31-69.31) than 5-year influenza and pneumonia rural-urban risk difference (12.57, 95% CI, 11.16-13.00) during 2015-2019. CONCLUSIONS: COVID-19 mortality rates were greater for populations living in Tennessee's rural as compared with urban counties during the study period. This differential impact must be considered in public health decision making to mitigate COVID-19.

A Frontal Account of False Alarms.

Prior research has demonstrated that the frontal lobes play a critical role in the top-down control of behavior, and damage to the frontal cortex impairs performance on tasks that require executive control [Burgess, P. W., & Stuss, D. T. Fifty years of prefrontal cortex research: Impact on assessment. Journal of the International Neuropsychological Society, 23, 755-767, 2017; Stuss, D. T., & Levine, B. Adult clinical neuropsychology: Lessons from studies of the frontal lobes. Annual Review of Psychology, 53, 401-433, 2002]. Across executive functioning tasks, performance deficits are often quantified as the number of false alarms per total number of nontarget trials. However, most studies of frontal lobe function focus on individual task performance and do not discuss commonalities of errors committed across different tasks. Here, we describe a neurocognitive account that explores the link between deficient frontal lobe function and increased false alarms across an array of experimental tasks from a variety of task domains. We review evidence for heightened false alarms following frontal deficits in episodic long-term memory tests, working memory tasks (e.g., n-back), attentional tasks (e.g., continuous performance tasks), interference control tasks (e.g., recent probes), and inhibitory control tasks (e.g., go/no-go). We examine this relationship via neuroimaging studies, lesion studies, and across age groups and pathologies that impact the pFC, and we propose 11 issues in cognitive processing that can result in false alarms. In our review, some overlapping neural regions were implicated in the regulation of false alarms. Ultimately, however, we find evidence for the fractionation and localization of certain frontal processes related to the commission of specific types of false alarms. We outline avenues for additional research that will enable further delineation of the fractionation of the frontal lobes' regulation of false alarms.

Age differences in functional network reconfiguration with working memory training.

Demanding cognitive functions like working memory (WM) depend on functional brain networks being able to communicate efficiently while also maintaining some degree of modularity. Evidence suggests that aging can disrupt this balance between integration and modularity. In this study, we examined how cognitive training affects the integration and modularity of functional networks in older and younger adults. Twenty three younger and 23 older adults participated in 10 days of verbal WM training, leading to performance gains in both age groups. Older adults exhibited lower modularity overall and a greater decrement when switching from rest to task, compared to younger adults. Interestingly, younger but not older adults showed increased task-related modularity with training. Furthermore, whereas training increased efficiency within, and decreased participation of, the default-mode network for younger adults, it enhanced efficiency within a task-specific salience/sensorimotor network for older adults. Finally, training increased segregation of the default-mode from frontoparietal/salience and visual networks in younger adults, while it diffusely increased between-network connectivity in older adults. Thus, while younger adults increase network segregation with training, suggesting more automated processing, older adults persist in, and potentially amplify, a more integrated and costly global workspace, suggesting different age-related trajectories in functional network reorganization with WM training.

Post-training stimulation of the right dorsolateral prefrontal cortex impairs working memory training performance.

Research investigating transcranial direct current stimulation (tDCS) to enhance cognitive training augments both our understanding of its long-term effects on cognitive plasticity as well as potential applications to strengthen cognitive interventions. Previous work has demonstrated enhancement of working memory training while applying concurrent tDCS to the dorsolateral prefrontal cortex (DLPFC). However, the optimal stimulation parameters are still unknown. For example, the timing of tDCS delivery has been shown to be an influential variable that can interact with task learning. In the present study, we used tDCS to target the right DLPFC while participants trained on a visuospatial working memory task. We sought to compare the relative efficacy of online stimulation delivered during training to offline stimulation delivered either immediately before or afterwards. We were unable to replicate previously demonstrated benefits of online stimulation; however, we did find evidence that offline stimulation delivered after training can actually be detrimental to training performance relative to sham. We interpret our results in light of evidence suggesting a role of the right DLPFC in promoting memory interference, and conclude that while tDCS may be a promising tool to influence the results of cognitive training, more research and an abundance of caution are needed before fully endorsing its use for cognitive enhancement. This work suggests that effects can vary substantially in magnitude and direction between studies, and may be heavily dependent on a variety of intervention protocol parameters such as the timing and location of stimulation delivery, about which our understanding is still nascent.

Targeted self-regulation interventions in low-income children: Clinical trial results and implications for health behavior change.

Self-regulation, known as the ability to harness cognitive, emotional, and motivational resources to achieve goals, is hypothesized to contribute to health behaviors across the lifespan. Enhancing self-regulation early in life may increase positive health outcomes. During pre-adolescence, children assume increased autonomy in health behaviors (e.g., eating; physical activity), many of which involve self-regulation. This article presents results from a clinical trial (NCT03060863) that used a factorial design to test behavioral interventions designed to enhance self-regulation, specifically targeting executive functioning, emotion regulation, future-oriented thinking, and approach biases. Participants were 118 children (9-12 years of age, M = 10.2 years) who had a history of living in poverty. They were randomized to receive up to four interventions that were delivered via home visits. Self-regulation was assayed using behavioral tasks, observations, interviews, and parent- and child-report surveys. Results were that self-regulation targets were reliably assessed and that interventions were delivered with high fidelity. Intervention effect sizes were very small to moderate (d range = .02-.65, median = .14), and most were not statistically significant. Intercorrelation analyses indicated that associations between measures within each target varied based on the self-regulation target evaluated. Results are discussed with regard to the role of self-regulation-focused interventions in child health promotion. Implications of findings are reviewed for informing next steps in behavioral self-regulation interventions among children from low-income backgrounds.

How to play 20 questions with nature and lose: Reflections on 100 years of brain-training research.

Despite dozens of empirical studies and a growing body of meta-analytic work, there is little consensus regarding the efficacy of cognitive training. In this review, we examine why this substantial corpus has failed to answer the often-asked question, "Does cognitive training work?" We first define cognitive training and discuss the general principles underlying training interventions. Next, we review historical interventions and discuss how findings from this early work remain highly relevant for current cognitive-training research. We highlight a variety of issues preventing real progress in understanding the underlying mechanisms of training, including the lack of a coherent theoretical framework to guide training research and methodological issues across studies and meta-analyses. Finally, suggestions for correcting these issues are offered in the hope that we might make greater progress in the next 100 y of cognitive-training research.

Expanding the Scope of Implicit Personality Assessment: An Examination of the Questionnaire-Based Implicit Association Test (qIAT).

Self-report questionnaires can only yield information that people are able and willing to report, but implicit assessment methods are not commonly used in mainstream personality research. The Questionnaire-based Implicit Association Test (qIAT) was designed to address the limitations associated with the conventional self-concept IAT, and it enables an indirect assessment that is based on the items of standard self-reports. The present studies examined the psychometric properties of the qIAT across two personality constructs. Study 1 (N = 528) provided support for the internal consistency, test-retest reliability and convergent and discriminant validity of the qIAT that measured extraversion. Study 2 (N = 164) supported the reliability and validity of the qIAT assessment of conscientiousness, which predicted who returned to complete the second session of the study two weeks later, for which participants were paid in advance. This same prediction effect was marginally significant in Study 3 (N = 200), and across both Studies 2 and 3 the qIAT prediction of the criterion behavior was incremental to the parallel self-report questionnaire. Taken together, findings support the reliability and validity of the qIAT, which enables the indirect measurement of a wide variety of distinct personality constructs, currently measured only by self-report scales.

How Do Older Adults Recruited Using MTurk Differ From Those in a National Probability Sample?

A growing number of studies within the field of gerontology have included samples recruited from Amazon's Mechanical Turk (MTurk), an online crowdsourcing portal. While some research has examined how younger adult participants recruited through other means may differ from those recruited using MTurk, little work has addressed this question with older adults specifically. In the present study, we examined how older adults recruited via MTurk might differ from those recruited via a national probability sample, the Health and Retirement Study (HRS), on a battery of outcomes related to health and cognition. Using a Latin-square design, we examined the relationship between recruitment time, remuneration amount, and measures of cognitive functioning. We found substantial differences between our MTurk sample and the participants within the HRS, most notably within measures of verbal fluency and analogical reasoning. Additionally, remuneration amount was related to differences in time to complete recruitment, particularly at the lowest remuneration level, where recruitment completion required between 138 and 485 additional hours. While the general consensus has been that MTurk samples are a reasonable proxy for the larger population, this work suggests that researchers should be wary of overgeneralizing research conducted with older adults recruited through this portal.

Patient alliance with the program predicts treatment outcomes whereas alliance with the therapist predicts adherence in internet-based therapy for panic disorder.

This study examines relationships among different aspects of therapeutic alliance with treatment outcome, adherence and attrition in internet delivered cognitive behavioral therapy (ICBT) for panic disorder.We examined alliance-outcome relationships in ICBT (N = 74) using a newly developed self-report alliance measure that disentangles alliance with program content (Internet Patient's Experience of Attunement and Responsiveness with the program; I-PEARp) and with the therapist (I-PEARt). We compared ICBT outcomes of patient rated and therapist-rated alliance with conventional alliance scales (WAI-6 and WAI-T).Consistent with our hypothesis, I-PEARp and I-PEARt distinguished between different aspects of the alliance and predicted outcomes better than standard alliance scales. Furthermore, higher ratings of I-PEARp were associated with subsequent lower symptoms and lower symptoms were associated with higher subsequent alliance. In contrast, I-PEARt predicted adherence, but not symptoms. Although therapists' ratings of alliance (thI-PEAR) improved significantly during treatment, they did not predict subsequent symptoms, adherence, or dropout.Results indicate that the patient experience of the alliance in ICBT includes two aspects, each of which uniquely contributes to outcomes; patient connection to the program is related to symptom outcomes whereas the dyadic relationship with the therapist serves as the glue to allow the treatment to hold.

Neural correlates of working memory training: Evidence for plasticity in older adults.

Brain activity typically increases with increasing working memory (WM) load, regardless of age, before reaching an apparent ceiling. However, older adults exhibit greater brain activity and reach ceiling at lower loads than younger adults, possibly reflecting compensation at lower loads and dysfunction at higher loads. We hypothesized that WM training would bolster neural efficiency, such that the activation peak would shift towards higher memory loads after training. Pre-training, older adults showed greater recruitment of the WM network than younger adults across all loads, with decline at the highest load. Ten days of adaptive training on a verbal WM task improved performance and led to greater brain responsiveness at higher loads for both groups. For older adults the activation peak shifted rightward towards higher loads. Finally, training increased task-related functional connectivity in older adults, both within the WM network and between this task-positive network and the task-negative/default-mode network. These results provide new evidence for functional plasticity with training in older adults and identify a potential signature of improvement at the neural level.

Pyrocinchonimides Conjugate to Amine Groups on Proteins via Imide Transfer.

Advances in bioconjugation, the ability to link biomolecules to each other, small molecules, surfaces, and more, can spur the development of advanced materials and therapeutics. We have discovered that pyrocinchonimide, the dimethylated analogue of maleimide, undergoes a surprising transformation with biomolecules. The reaction targets amines and involves an imide transfer, which has not been previously reported for bioconjugation purposes. Despite their similarity to maleimides, pyrocinchonimides do not react with free thiols. Though both lysine residues and the N-termini of proteins can receive the transferred imide, the reaction also exhibits a marked preference for certain amines that cannot solely be ascribed to solvent accessibility. This property is peculiar among amine-targeting reactions and can reduce combinatorial diversity when many available reactive amines are available, such as in the formation of antibody-drug conjugates. Unlike amides, the modification undergoes very slow reversion under high pH conditions. The reaction offers a thermodynamically controlled route to single or multiple modifications of proteins for a wide range of applications.

Adolescent Interventions to Manage Self-Regulation in Type 1 Diabetes (AIMS-T1D): randomized control trial study protocol.

BACKGROUND: Self-regulation (SR), or the capacity to control one's thoughts, emotions, and behaviors in order to achieve a desired goal, shapes health outcomes through many pathways, including supporting adherence to medical treatment regimens. Type 1 Diabetes (T1D) is one specific condition that requires SR to ensure adherence to daily treatment regimens that can be arduous and effortful (e.g., monitoring blood glucose). Adolescents, in particular, have poor adherence to T1D treatment regimens, yet it is essential that they assume increased responsibility for managing their T1D as they approach young adulthood. Adolescence is also a time of rapid changes in SR capacity and thus a compelling period for intervention. Promoting SR among adolescents with T1D may thus be a novel method to improve treatment regimen adherence. The current study tests a behavioral intervention to enhance SR among adolescents with T1D. SR and T1D medical regimen adherence will be examined as primary and secondary outcomes, respectively. METHODS: We will use a randomized control trial design to test the impact of a behavioral intervention on three SR targets: Executive Functioning (EF), Emotion Regulation (ER), and Future Orientation (FO); and T1D medical regimen adherence. Adolescents with T1D (n = 94) will be recruited from pediatric endocrinology clinics and randomly assigned to treatment or control group. The behavioral intervention consists of working memory training (to enhance EF), biofeedback and relaxation training (to enhance ER), and episodic future thinking training (to enhance FO) across an 8-week period. SR and treatment regimen adherence will be assessed at pre- and post-test using multiple methods (behavioral tasks, diabetes device downloads, self- and parent-report). We will use an intent-to-treat framework using generalized linear mixed models to test our hypotheses that: 1) the treatment group will demonstrate greater improvements in SR than the control group, and 2) the treatment group will demonstrate better treatment regimen adherence outcomes than the control group. DISCUSSION: If successful, SR-focused behavioral interventions could improve health outcomes among adolescents with T1D and have transdiagnostic implications across multiple chronic conditions requiring treatment regimen adherence. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03688919; registered September 28, 2018.