The FMR1 premutation (PM) is relatively common in the general population. Evidence suggests that PM carriers may exhibit subtle differences in specific cognitive and language abilities. This study ...examined potential mechanisms underlying such differences through the study of gaze and language coordination during a language processing task (rapid automatized naming; RAN) among female carriers of the FMR1 PM. RAN taps a complex set of underlying neuropsychological mechanisms, with breakdowns implicating processing disruptions in fundamental skills that support higher order language and executive functions, making RAN (and analysis of gaze/language coordination during RAN) a potentially powerful paradigm for revealing the phenotypic expression of the FMR1 PM. Forty-eight PM carriers and 56 controls completed RAN on an eye tracker, where they serially named arrays of numbers, letters, colors, and objects. Findings revealed a pattern of inefficient language processing in the PM group, including a greater number of eye fixations (namely, visual regressions) and reduced eye-voice span (i.e., the eyes' lead over the voice) relative to controls. Differences were driven by performance in the latter half of the RAN arrays, when working memory and processing load are the greatest, implicating executive skills. RAN deficits were associated with broader social-communicative difficulties among PM carriers, and with FMR1-related molecular genetic variation (higher CGG repeat length, lower activation ratio, and increased levels of the fragile X mental retardation protein; FMRP). Findings contribute to an understanding of the neurocognitive profile of PM carriers and indicate specific gene-behavior associations that implicate the role of the FMR1 gene in language-related processes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alu elements are the most abundant source of nonallelic homology that influences genetic instability in the human genome. When there is a DNA double‐stranded break, the Alu element's high copy ...number, moderate length and distance and mismatch between elements uniquely influence recombination processes. We utilize a reporter‐gene assay to show the complex influence of Alu mismatches on Alu‐related repeat‐mediated deletions (RMDs). The Alu/Alu heteroduplex intermediate can result in a nonallelic homologous recombination (HR). Alternatively, the heteroduplex can result in various DNA breaks around the Alu elements caused by competing nucleases. These breaks can undergo Alt‐nonhomologous end joining to cause deletions focused around the Alu elements. Formation of these heteroduplex intermediates is largely RAD52 dependent. Cells with low ERCC1 levels utilize more of these alternatives resolutions, while cells with MSH2 defects tend to have more RMDs with a specific increase in the HR events. Therefore, Alu elements are expected to create different forms of deletions in various cancers depending on a number of these DNA repair defects.
Given the prevalence of racism in the United States that has led to the increase of adverse mental health outcomes and disparities in care among African Americans, ethnic-racial identity (ERI) is a ...significant cultural resource that may be beneficial in understanding African American's mental health outcomes. This narrative review aimed to summarize and synthesize the existing literature on the associations between African Americans' ERI and mental health outcomes, highlighting the developmental periods, types of mental health symptoms, and types of promotive mental health-related behaviors (MHRBs) that have been studied to date. Twenty-six peer-reviewed, empirical studies met the inclusion criteria. Results indicated that affirmation/private regard and positive public regard were mainly associated with less anxiety and depressive symptoms among emerging adults and adults. Centrality revealed inconclusive associations with mental health symptoms. Additionally, centrality and public and private regard have been associated with the use of promotive MHRBs among adults. Exploration and resolution were mainly associated with fewer mental health symptoms among emerging adults. Overall, ERI plays a key role in African Americans' mental health outcomes and reveals important implications for interventions.
Abstract
Fetal aging (FA) is an assisted reproductive technique in which fetal measurements collected via transrectal ultrasonography are used to estimate the day of gestation of a fetus. These ...estimations can then be used to generate calving date predictions, which allow producers to capitalize on the management of both pregnant and non-pregnant females to improve reproductive efficiency and profitability. Previous literature supports the accuracy of calving date predictions when fetometry is used to generate fetal age. However, there is little published research validating the accuracy of fetal aging based on technician evaluation of the fetus at the time of ultrasound. The objectives of this study were to evaluate the accuracy of calving dates predicted with subjective FA compared with the accuracy of calving dates predicted using estrus detection methods (ED). Breeding cows (n = 130) ranging in both breed composition and parity were observed for visual signs of estrus twice daily from December 2021 through February 2022. Cattle were bred via natural service, and all observed signs of estrus and copulation were recorded and used to generate calving date predictions. Cattle were palpated for pregnancy via transrectal ultrasound in April 2022, at which time subjective estimations of fetal age were recorded by ultrasound technicians and used to generate calving date predictions. Data were analyzed using SAS version 9.4 with prediction method serving as the fixed effect. Of the cattle enrolled in this study, calving date predictions were generated from 91 cows using ED and 130 cows using FA. Data analysis indicated a strong positive correlation (Spearman) between FA calving date predictions compared with reported calving dates (r = 0.79, P ≤ 0.01), as compared with a moderately positive correlation between ED calving date predictions and reported calving dates (r = 0.59, P ≤ 0.01). When stratified according to estimated fetal age, analysis indicated a moderately positive correlation between FA calving date predictions and reported calving dates for short- (r = 0.58, P = 0.01) and mid- (r = 0.60, P ≤ 0.01) bred groups, and a weak positive correlation for the long-bred group (r = 0.17, P = 0.16). Data in this study indicates that FA calving date predictions were more accurate than ED calving date predictions. Further analysis will be conducted to quantify the economic value of FA as a method of calving date prediction for producers.
The dysregulated phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway has been implicated in various immune-mediated inflammatory and hyperproliferative ...dermatoses such as acne, atopic dermatitis, alopecia, psoriasis, wounds, and vitiligo, and is associated with poor treatment outcomes. Improved comprehension of the consequences of the dysregulated PI3K/Akt/mTOR pathway in patients with inflammatory dermatoses has resulted in the development of novel therapeutic approaches. Nonetheless, more studies are necessary to validate the regulatory role of this pathway and to create more effective preventive and treatment methods for a wide range of inflammatory skin diseases. Several studies have revealed that certain natural products and synthetic compounds can obstruct the expression/activity of PI3K/Akt/mTOR, underscoring their potential in managing common and persistent skin inflammatory disorders. This review summarizes recent advances in understanding the role of the activated PI3K/Akt/mTOR pathway and associated components in immune-mediated inflammatory dermatoses and discusses the potential of bioactive natural products, synthetic scaffolds, and biologic agents in their prevention and treatment. However, further research is necessary to validate the regulatory role of this pathway and develop more effective therapies for inflammatory skin disorders.
A benzoate CoA ligase (BadA), isolated from the bacterium Rhodopseudomonas palustris, catalyzes the conversion of benzoate to benzoyl CoA on the catabolic pathway of aromatic carboxylic acids. ...Herein, apparent Michaelis constants k cat app and K M app were determined for an expanded array of 31 substrates chosen to systematically probe the active site architecture of the enzyme and provide a baseline for expansion of wild-type substrate specificity. Acyl CoA products were observed for 25 of the 31 substrates; in general, BadA converted ortho-substituted substrates better than the corresponding meta and para regioisomers, and the turnover number was more affected by steric rather than electronic effects. The kinetic data are interpreted in relation to six crystal structures of BadA in complex with several substrates and a benzoyl-AMP reaction intermediate. In contrast to other known natural substrate-bound benzoate ligase structures, all substrate-bound BadA structures adopted the thiolation conformation instead of the adenylation conformation. We also observed all the aryl carboxylates to be uniquely oriented within the active site, relative to other structures. Together, the kinetics and structural data suggested a mechanism that involves substrate binding in the thiolation conformation, followed by substrate rotation to an active orientation upon the transition to the adenylation conformation. On the basis of this hypothesis and the structural data, sterically demanding active site residues were mutated, and the substrate specificity was expanded substantially versus that of BadA. Novel activities were seen for substrates with larger substituents, including phenyl acetate. Additionally, the mutant Lys427Ala identified this nonconserved residue as essential for the thiolation step of BadA, but not adenylation. These variously acylated CoAs can serve as novel substrates of acyl CoA-dependent acyltransferases in coupled enzyme assays to produce analogues of bioactive natural products.
Abstract
Accelerating the design and implementation of environmental flows (e-flows) is essential to curb the rapid, ongoing loss of freshwater biodiversity and the benefits it provides to people. ...However, the effectiveness of e-flow programs may be limited by a singular focus on ensuring adequate flow conditions at local sites, which overlooks the role of other ecological processes. Recent advances in metasystem ecology have shown that biodiversity patterns and ecosystem functions across river networks result from the interplay of local (environmental filtering and biotic interactions) and regional (dispersal) ecological processes. No guidelines currently exist to account for these processes in designing e-flows. We address this gap by providing a step-by-step operational framework that outlines how e-flows can be designed to conserve or restore metasystem dynamics. Our recommendations are relevant to diverse regulatory contexts and can improve e-flow outcomes even in basins with limited in situ data.
Rationale
Once dependent on alcohol or opioids, negative affect may accompany withdrawal. Dependent individuals are hypothesized to “self-medicate” in order to cope with withdrawal, which promotes ...escalated alcohol and drug use.
Objectives
The current study aimed to develop a reliable animal model to assess symptoms that occur during spontaneous alcohol and opioid withdrawal.
Methods
Dependence was induced using intermittent alcohol exposure or pulsatile heroin delivery and assessed for the presence of withdrawal symptoms during acute withdrawal by measuring somatic signs, behavior in the forced swim test (FST), and air-puff-induced 22-kHz ultrasonic vocalizations (USVs). Additional animals subjected to 8 weeks of alcohol vapor exposure were evaluated for altered somatic signs, operant alcohol self-administration, and 22-kHz USV production, as well as performance in the elevated plus maze (EPM).
Results
During spontaneous withdrawal from pulsatile heroin or intermittent alcohol vapor, animals displayed increased somatic withdrawal signs, FST immobility, and 22-kHz USV production but did not show any behavioral change in the EPM unless the duration of alcohol exposure was extended to 4 weeks. Following 8 weeks of alcohol vapor exposure, animals displayed somatic withdrawal signs, escalated alcohol self-administration, and increased 22-kHz USVs.
Conclusions
These paradigms provide consistent methods to evaluate the behavioral ramifications, and neurobiological substrates, of alcohol and opioid dependence during spontaneous withdrawal. As immobility in the FST and percent open-arm time in the EPM were dissociable, with 22-kHz USVs paralleling immobility in the FST, assessment of air-puff-induced 22-kHz USVs could provide an ethologically valid alternative to the FST.
Excessive alcohol use and problems during college is a major public health concern, and there are health disparities in patterns of drinking and alcohol-related illnesses based on ethnicity and race. ...Given the prevalence and disparities in excessive alcohol use and problems and associated negative impacts, it is important to examine potential protective factors such as dimensions of ethnic-racial identity (ERI). Thus, the current study examined how multiple dimensions of ERI were associated with alcohol use and alcohol use disorder (AUD) symptoms, and how these relations varied by individuals' ethnic-racial group among 1850 diverse emerging adults (M = 18.46, SD = .38). Findings indicated that there were significant differences by race/ethnicity. ERI affirmation was negatively associated with AUD symptoms for Asian individuals and African American individuals, while ERI exploration was positively associated with AUD symptoms among African American individuals. ERI resolution was negatively associated with alcohol use for Latinx individuals and positively associated with alcohol use for Multiracial individuals. Among White individuals, ERI exploration was negatively associated with alcohol use and ERI affirmation was negatively associated with AUD symptoms. Overall, the current study builds on our understanding of nuanced ways in which ethnic-racial identity impacts alcohol problems among emerging adults and highlights areas for future research.
Interprofessional education (IPE) activities provide students insight into healthcare teams, shared decision-making, and social determinants of health (SDOH). Virtual IPE activities with large ...student populations or across multicampus have not been evaluated. The study aimed to explore the interprofessional competency growth in students, across several disciplines, following participation in a large-scale, virtual IPE activity. Students from pharmacy, medicine, social work, and physician assistant programs across Tennessee participated in an IPE patient case and SDOH in fall 2020 and fall 2021. Pre- and postsurveys included Likert ranking of 16 statements based on the 2011 Interprofessional Education Collaborative (IPEC) framework. A total of 607 students completed surveys (overall response rate, 76%). Wilcoxon signed-rank tests were performed on the pre-/postsurvey data, in aggregate and by discipline. Significant increases in all IPEC competency statements were seen, both in aggregate (100% of statements with p < 0.001) and in pharmacy (100% of statements with p < 0.001) and medicine subgroups (94% of statements with p < 0.001). Implementing large virtual IPE activities involving a complex patient case and SDOH significantly increased student IPEC competency outcomes for participating students, whether in aggregate or on a discipline-specific basis.
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