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1.
PLoS Genet ; 19(2): e1010653, 2023 02.
Article in English | MEDLINE | ID: mdl-36795790

ABSTRACT

Animal traits develop through the expression and action of numerous regulatory and realizator genes that comprise a gene regulatory network (GRN). For each GRN, its underlying patterns of gene expression are controlled by cis-regulatory elements (CREs) that bind activating and repressing transcription factors. These interactions drive cell-type and developmental stage-specific transcriptional activation or repression. Most GRNs remain incompletely mapped, and a major barrier to this daunting task is CRE identification. Here, we used an in silico method to identify predicted CREs (pCREs) that comprise the GRN which governs sex-specific pigmentation of Drosophila melanogaster. Through in vivo assays, we demonstrate that many pCREs activate expression in the correct cell-type and developmental stage. We employed genome editing to demonstrate that two CREs control the pupal abdomen expression of trithorax, whose function is required for the dimorphic phenotype. Surprisingly, trithorax had no detectable effect on this GRN's key trans-regulators, but shapes the sex-specific expression of two realizator genes. Comparison of sequences orthologous to these CREs supports an evolutionary scenario where these trithorax CREs predated the origin of the dimorphic trait. Collectively, this study demonstrates how in silico approaches can shed novel insights on the GRN basis for a trait's development and evolution.


Subject(s)
Drosophila melanogaster , Gene Regulatory Networks , Animals , Male , Female , Drosophila melanogaster/genetics , Drosophila/genetics , Transcription Factors/genetics , Pigmentation/genetics
2.
J Magn Reson Imaging ; 2024 May 04.
Article in English | MEDLINE | ID: mdl-38703134

ABSTRACT

BACKGROUND: Cartilage T2 can detect joints at risk of developing osteoarthritis. The quantitative double-echo steady state (qDESS) sequence is attractive for knee cartilage T2 mapping because of its acquisition time of under 5 minutes. Understanding the reproducibility errors associated with qDESS T2 is essential to profiling the technical performance of this biomarker. PURPOSE: To examine the combined acquisition and segmentation reproducibility of knee cartilage qDESS T2 using two different regional analysis schemes: 1) manual segmentation of subregions loaded during common activities and 2) automatic subregional segmentation. STUDY TYPE: Prospective. SUBJECTS: 11 uninjured participants (age: 28 ± 3 years; 8 (73%) female). FIELD STRENGTH/SEQUENCE: 3-T, qDESS. ASSESSMENT: Test-retest T2 maps were acquired twice on the same day and with a 1-week interval between scans. For each acquisition, average cartilage T2 was calculated in four manually segmented regions encompassing tibiofemoral contact areas during common activities and 12 automatically segmented regions from the deep-learning open-source framework for musculoskeletal MRI analysis (DOSMA) encompassing medial and lateral anterior, central, and posterior tibiofemoral regions. Test-retest T2 values from matching regions were used to evaluate reproducibility. STATISTICAL TESTS: Coefficients of variation (%CV), root-mean-square-average-CV (%RMSA-CV), and intraclass correlation coefficients (ICCs) assessed test-retest T2 reproducibility. The median of test-retest standard deviations was used for T2 precision. Bland-Altman (BA) analyses examined test-retest biases. The smallest detectable difference (SDD) was defined as the BA limit of agreement of largest magnitude. Significance was accepted for P < 0.05. RESULTS: All cartilage regions across both segmentation schemes demonstrated intraday and interday qDESS T2 CVs and RMSA-CVs of ≤5%. T2 ICC values >0.75 were observed in the majority of regions but were more variable in interday tibial comparisons. Test-retest T2 precision was <1.3 msec. The T2 SDD was 3.8 msec. DATA CONCLUSION: Excellent CV and RMSA-CV reproducibility may suggest that qDESS T2 increases or decreases >5% (3.8 msec) could represent changes to cartilage composition. TECHNICAL EFFICACY: Stage 2.

3.
Langmuir ; 40(1): 211-220, 2024 Jan 09.
Article in English | MEDLINE | ID: mdl-38154121

ABSTRACT

Surfactants provide detergency, foaming, and texture in personal care formulations, yet the micellization of typical industrial primary and cosurfactants is not well understood, particularly in light of the polydisperse nature of commercial surfactants. Synergistic interactions are hypothesized to drive the formation of elongated wormlike self-assemblies in these mixed surfactant systems. Small-angle neutron scattering, rheology, and pendant drop tensiometry are used to examine surface adsorption, viscoelasticity, and self-assembly structure for wormlike micellar formulations comprising cocoamidopropyl betaine, and its two major components laurylamidopropyl betaine and oleylamidopropyl betaine, with sodium alkyl ethoxy sulfates. The tail length of sodium alkyl ethoxy sulfates was related to their ability to form wormlike micelles in electrolyte solutions, indicating that a tail length greater than 10 carbons is required to form wormlike micelles in NaCl solutions, with the decyl homologue unable to form elongated micelles and maintaining a low viscosity even at 20 wt % surfactant loading with 4 wt % NaCl present. For these systems, the incorporation of a disperse ethoxylate linker does not enable shorter chain surfactants to elongate into wormlike micelles for single-component systems; however, it could increase the interactions between surfactants in mixed surfactant systems. For synergy in surfactant mixing, the nonideal regular solution theory is used to study the sulfate/betaine mixtures. Tail mismatch appears to drive lower critical micelle concentrations, although tail matching improves synergy with larger relative reductions in critical micelle concentrations and greater micelle elongation, as seen by both tensiometric and scattering measurements.

4.
J Surg Res ; 300: 205-210, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38824850

ABSTRACT

INTRODUCTION: Various factors impact outcomes following bariatric surgery. Lack of access to healthy food options (food insecurity [FI]) is another potential factor affecting outcomes. No prior studies have directly explored the relationship between residing in a high FI zip code and patient outcomes relating to weight loss after bariatric surgery. We hypothesized that living in a high FI zip code would be associated with decreased weight loss postsurgery. METHODS: We conducted a retrospective study with 210 bariatric surgery patients at a tertiary referral center from January to December 2020. Patient weight and body mass index (BMI) were recorded at three time points: surgery date, 1 mo, and 12 mo postoperative. Residential addresses were collected, and FI rates for the corresponding Zip Code Tabulation Areas were obtained from the 2022 Feeding America Map the Meal Gap study (2020 data). RESULTS: The FI rate showed a negative correlation of -18.3% (95% confidence interval: -35% to -0.5%; P = 0.039) with the percentage of excess weight loss (%EWL) at 1 y. In multivariate analysis, preoperative BMI (P = 0.001), presence of diabetes mellitus (P = 0.008), and bariatric procedure type (P = 0.000) were significant predictors of %EWL at 1 y. After adjusting for confounding factors, including sex, preoperative BMI, insurance status, primary bariatric procedure, and emergency department visits, the increased FI rate (P = 0.047) remained significantly associated with a decreased %EWL at 1 y. CONCLUSIONS: Residing in a high FI, Zip Code Tabulation Areas correlated with a decreased %EWL at 1 y after bariatric surgery. These findings highlight the importance of assessing FI status in pre-bariatric surgery patients and providing additional support to individuals facing FI.

5.
Article in English | MEDLINE | ID: mdl-38531639

ABSTRACT

BACKGROUND: No data exist at the population level on what tests are used to aid in the diagnosis of autism spectrum disorder in community practice. OBJECTIVES: To describe autism spectrum disorder testing practices to inform autism spectrum disorder identification efforts. METHODS: Data are from the Autism and Developmental Disabilities Monitoring Network, a multi-site surveillance system reporting prevalence estimates and characteristics of 8-year-old children with autism spectrum disorder. Percentages of children with autism spectrum disorder who received any autism spectrum disorder test or a 'gold standard' test were calculated by site, sex, race, median household income, and intellectual ability status. Risk ratios were calculated to compare group differences. RESULTS: Of 5058 8-year-old children with autism spectrum disorder across 11 sites, 3236 (64.0%) had a record of any autism spectrum disorder test and 2136 (42.2%) had a 'gold standard' ADOS or ADI-R test. Overall, 115 children (2.3%) had both the ADOS and ADI-R in their records. Differences persisted across race, median household income, and intellectual ability status. Asian/Pacific Islander children had the highest percent receiving any ASD test (71.8%; other groups range: 57.4-66.0%) and White children had the highest percent receiving 'gold standard' tests (46.4%; other groups range: 35.6-43.2%). Children in low-income neighbourhoods had a lower percent of any test (62.5%) and 'gold standard' tests (39.4%) compared to medium (70.2% and 47.5%, respectively) and high (69.6% and 46.8%, respectively) income neighbourhoods. Children with intellectual disability had a lower percent of any ASD test (81.7%) and 'gold standard' tests (52.6%) compared to children without intellectual disability (84.0% and 57.6%, respectively). CONCLUSIONS: Autism spectrum disorder testing practices vary widely by site and differ by race and presence of co-occurring intellectual disability, suggesting opportunities to standardise and/or improve autism spectrum disorder identification practices.

6.
Article in English | MEDLINE | ID: mdl-38193943

ABSTRACT

PURPOSE: We sought to identify trends and characteristics associated with the availability of tailored mental health services for individuals involved in the criminal justice system and ordered to treatment by a court, nationally in the US and by state. METHODS: We used National Mental Health Services Survey to identify outpatient mental health treatment facilities in the US (2016 n = 4744; 2018 n = 4626; 2020 n = 4869). We used clustered multiple logistic regression to identify changes over time as well as facility- and state-level factors associated with the availability of specialty court-ordered services. RESULTS: Slightly more than half of the outpatient mental health treatment facilities offered specialized services for individuals ordered to treatment by a court, with wide variation between states. Nationally, there was a significant increase in the odds of offering court-ordered treatment in 2020 compared to 2016 (aOR = 1.16, 95% CI = 1.06-1.27, p < 0.01). Notable associations included offering integrated substance use treatment (versus none, aOR = 2.95, 95% CI = 2.70-3.22, p < 0.0001) and offering trauma therapy (versus none, aOR = 2.05, 95% CI = 1.85-2.27, p < 0.0001). CONCLUSION: The availability of mental health services for individuals ordered to treatment by a court is growing nationally but several states are lagging behind. Court ordered treatment is a promising strategy to improve health and reduce reliance on the carceral system as a healthcare provider. At the same time, we express caution around disparities within behavioral health courts and advocate for equity in access to incarceration alternatives.

7.
Chemistry ; 29(14): e202202902, 2023 Mar 07.
Article in English | MEDLINE | ID: mdl-36440875

ABSTRACT

De novo metalloprotein design involves the construction of proteins guided by specific repeat patterns of polar and apolar residues, which, upon self-assembly, provide a suitable environment to bind metals and produce artificial metalloenzymes. While a wide range of functionalities have been realized in de novo designed metalloproteins, the functional repertoire of such constructs towards alternative energy-relevant catalysis is currently limited. Here we show the application of de novo approach to design a functional H2 evolving protein. The design involved the assembly of an amphiphilic peptide featuring cysteines at tandem a/d sites of each helix. Intriguingly, upon NiII addition, the oligomers shift from a major trimeric assembly to a mix of dimers and trimers. The metalloprotein produced H2 photocatalytically with a bell-shape pH dependence, having a maximum activity at pH 5.5. Transient absorption spectroscopy is used to determine the timescales of electron transfer as a function of pH. Selective outer sphere mutations are made to probe how the local environment tunes activity. A preferential enhancement of activity is observed via steric modulation above the NiII site, towards the N-termini, compared to below the NiII site towards the C-termini.


Subject(s)
Metalloproteins , Metalloproteins/chemistry , Hydrogen , Metals , Cysteine/chemistry , Peptides/chemistry
8.
Eur J Clin Microbiol Infect Dis ; 42(6): 747-757, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37084119

ABSTRACT

Invasive Group B Streptococcus (GBS) can infect pregnant women, neonates, and older adults. Invasive GBS serotype VIII is infrequent in Alberta; however, cases have increased in recent years. Here, genomic analysis was used to characterize fourteen adult invasive serotype VIII isolates from 2009 to 2021. Trends in descriptive clinical data and antimicrobial susceptibility results were evaluated for invasive serotype VIII isolates from Alberta. Isolate genomes were sequenced and subjected to molecular sequence typing, virulence and antimicrobial resistance gene identification, phylogenetic analysis, and pangenome determination. Multilocus sequencing typing identified eight ST42 (Clonal Complex; CC19), four ST1 (CC1), and two ST2 (CC1) profiles. Isolates were susceptible to penicillin, erythromycin, chloramphenicol, and clindamycin, apart from one isolate that displayed erythromycin and inducible clindamycin resistance. All isolates carried genes for peptide antibiotic resistance, three isolates for tetracycline resistance, and one for macrolide, lincosamide, and streptogramin resistance. All genomes carried targets currently being considered for protein-based vaccines (e.g., pili and/or Alpha family proteins). Overall, invasive GBS serotype VIII is emerging in Alberta, primarily due to ST42. Characterization and continued surveillance of serotype VIII will be important for outbreak prevention, informing vaccine development, and contributing to our understanding of the global epidemiology of this rare serotype.


Subject(s)
Clindamycin , Streptococcal Infections , Infant, Newborn , Humans , Female , Pregnancy , Aged , Serogroup , Clindamycin/therapeutic use , Streptococcus agalactiae , Streptococcal Infections/microbiology , Alberta/epidemiology , Phylogeny , Multilocus Sequence Typing , Drug Resistance, Bacterial , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Erythromycin/therapeutic use , Genomics , Microbial Sensitivity Tests
9.
Child Dev ; 94(5): 1205-1221, 2023.
Article in English | MEDLINE | ID: mdl-37547951

ABSTRACT

Studies show that spatial interventions lead to improvements in mathematics. However, outcomes vary based on whether physical manipulatives (embodied action) are used during training. This study compares the effects of embodied and non-embodied spatial interventions on spatial and mathematics outcomes. The study has a randomized, controlled, pre-post, follow-up, training design (N = 182; mean age 8 years; 49% female; 83.5% White). We show that both embodied and non-embodied spatial training approaches improve spatial skills compared to control. However, we conclude that embodied spatial training using physical manipulatives leads to larger, more consistent gains in mathematics and greater depth of spatial processing than non-embodied training. These findings highlight the potential of spatial activities, particularly those that use physical materials, for improving children's mathematics skills.


Subject(s)
Parent-Child Relations , Child , Humans , Female , Male , Mathematics
10.
Ann Plast Surg ; 90(5): 444-446, 2023 05 01.
Article in English | MEDLINE | ID: mdl-36913562

ABSTRACT

INTRODUCTION: The necessity of treating hypertrophic burn scars has expanded significantly with increased burn survivorship. Ablative lasers, such as carbon dioxide (CO 2 ) lasers, have been the most common nonoperative option for improving functional outcomes in severe recalcitrant hypertrophic burn scars. However, the overwhelming majority of ablative lasers used for this indication require a combination of systemic analgesia, sedation, and/or general anesthesia due to the painful nature of the procedure. More recently, the technology of ablative lasers has advanced and is more tolerable than their first-generation counterparts. Herein, we hypothesized that refractory hypertrophic burn scars can be treated by a CO 2 laser in an outpatient clinic. METHODS: We enrolled 17 consecutive patients with chronic hypertrophic burn scars that were treated with a CO 2 laser. All patients were treated in the outpatient clinic with a combination of a topical solution (23% lidocaine and 7% tetracaine) applied to the scar 30 minutes before the procedure, Cryo 6 air chiller by Zimmer, and some patients received a mixture of N 2 O/O 2 . Laser treatments were repeated every 4 to 8 weeks until the patient's goals were met. Each patient completed a standardized questionnaire to assess tolerability and patient satisfaction of functional results. RESULTS: All patients tolerated the laser well in the outpatient clinic setting, with 0% indicating "not tolerable," 70.6% "tolerable," and 29.4% "very tolerable." Each patient received more than 1 laser treatment for the following complaints: decreased range of motion (n = 16, 94.1%), pain (n = 11, 64.7%), or pruritis (n = 12, 70.6%). Patients were also satisfied with the results of the laser treatments ("no improvement or worsened" = 0%, "improved" = 47.1%, and "significant improvement" = 52.9%). The age of patient, type of burn, location of burn, presence of skin graft, or age of scar did not significantly affect the tolerability of treatment or satisfaction of outcome. CONCLUSIONS: The treatment of chronic hypertrophic burn scars with a CO 2 laser is well tolerated in an outpatient clinic setting in select patients. Patients reported a high level of satisfaction with notable improvement in functional and cosmetic outcomes.


Subject(s)
Burns , Cicatrix, Hypertrophic , Lasers, Gas , Humans , Cicatrix/etiology , Cicatrix/surgery , Cicatrix/pathology , Cicatrix, Hypertrophic/etiology , Cicatrix, Hypertrophic/surgery , Hypertrophy , Skin/pathology , Lasers, Gas/therapeutic use , Burns/complications , Burns/surgery , Treatment Outcome
11.
Article in English | MEDLINE | ID: mdl-38016487

ABSTRACT

OBJECTIVE: The development of serious games for mental wellbeing is a topic of growing interest. The increase in acceptance of games as a mainstream entertainment medium combined with the immersive qualities of games provides opportunities for meaningful support and intervention in mental wellbeing. METHOD: We conducted a systematic review and exploratory meta-analysis to examine if aspects of the interventions influenced outcomes as measured via overall effect sizes. We employed a multilevel meta-analytic approach to accommodate the interdependency of effect sizes (18 effect sizes from 14 studies, with 2027 participants). RESULTS: Overall, the main effect for gaming interventions on any outcome variable was small to medium sized, d = .35 (confidence interval [.23, 47], p < .001). Results revealed that the only significant moderator was the nature of the intervention. Specifically, only interventions that included a rational emotional behavioural focus significantly predicted an improvement in depression and/or anxiety in participants. CONCLUSION: The findings reveal promising effects for therapeutic games for mental health, but replications are needed, alongside the addressing of methodological and procedural concerns.

12.
J Exp Biol ; 225(22)2022 11 15.
Article in English | MEDLINE | ID: mdl-36239066

ABSTRACT

Reproduction and environmental stressors are generally thought to be associated with a cost to the individual experiencing them, but the physiological mechanisms mediating costs of reproduction and maternal effects remain poorly understood. Studies examining the effects of environmental stressors on a female's physiological state and body condition during reproduction, as well as the physiological condition of offspring, have yielded equivocal results. Mitochondrial physiology and oxidative stress have been implicated as important mediators of life-history trade-offs. The goal of this investigation was to uncover the physiological mechanisms responsible for the enhanced trade-off between self-maintenance and offspring investment when an animal is exposed to stressful conditions during reproduction. To that end, we manipulated circulating corticosterone (CORT) levels by orally supplementing lactating female mice with CORT and investigated mitochondrial physiology and oxidative stress of both the reproductive females and their young. We found that maternal CORT exposure resulted in lower litter mass at weaning, but mitochondrial performance and oxidative status of females were not impacted. We also found potential beneficial effects of maternal CORT on mitochondrial function (e.g. higher respiratory control ratio) and oxidative stress (e.g. lower reactive oxygen species production) of offspring in adulthood, suggesting that elevated maternal CORT may be a signal for early-life adversity and prepare the organism with a predictive, adaptive response to future stressors.


Subject(s)
Corticosterone , Lactation , Animals , Female , Mice , Corticosterone/pharmacology , Reproduction/physiology , Oxidative Stress , Mitochondria
13.
Phys Chem Chem Phys ; 24(19): 11713-11720, 2022 May 18.
Article in English | MEDLINE | ID: mdl-35506511

ABSTRACT

The potential formation of halogen bonded complexes between a donor, heptafluoro-2-iodopropane (HFP), and the three acceptor heterocyclic azines (azabenzenes: pyridine, pyrimidine, and pyridazine) is investigated herein through normal mode analysis via Raman spectroscopy, density functional theory, and natural electron configuration analysis. Theoretical Raman spectra of the halogen bonded complexes are in good agreement with experimental data providing insight into the Raman spectra of these complexes. The exhibited shifts in vibrational frequency of as high as 8 cm-1 for each complex demonstrate, in conjunction with NEC analysis, significant evidence of charge transfer from the halogen bond acceptor to donor. Here, an interesting charge flow mechanism is proposed involving the donated nitrogen lone pair electrons pushing the dissociated fluorine atoms back to their respective atoms. This mechanism provides further insight into the formation and fundamental nature of halogen bonding and its effects on neighboring atoms. The present findings provide novel and deeper characterization of halogen bonding with applications in supramolecular and organometallic chemistry.

14.
J Fish Biol ; 100(6): 1475-1496, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35394647

ABSTRACT

Marine resources are often shared among countries, with some fish stocks straddling multiple Exclusive Economic Zones, therefore understanding the structure of populations is important for the effective management of fish stocks. Otolith chemical analyses could discriminate among populations based on differences in the chemical composition of otoliths. We used otoliths from two deepwater snappers (flame snapper Etelis coruscans and ruby snapper Etelis boweni) to examine the evidence for population structure across six Pacific Island countries using solution-based inductively coupled plasma mass spectrometry (ICP-MS) for otolith core and whole otolith samples and laser ablation ICP-MS (LA-ICP-MS) for core and edge areas of a cross-sectioned otolith. The inter-species comparison of these methods is important as the two species are often managed under the same regulations. For both species, the two methods demonstrated separation among the locations sampled with high classification accuracy. Smaller laser ablation spot size gave greater temporal resolution over the life-history transect. Comparing the early life-history section of the otoliths (i.e., the core), one interpretation is that young fish experienced more uniform environments in the open ocean as larvae than adults, as the elemental fingerprints had greater overlap among multiple locations. LA-ICP-MS methods had some advantages over solution-based ICP-MS and generally better discrimination for the trace elements investigated. There were substantial differences between species, but both methods suggested nonmixing populations at the regional scale. Otolith chemistry can be an effective tool in discriminating variation for deepwater marine species in multispecies fisheries, and edge measurements from LA-ICP-MS provided the greatest resolution. Although caution should be taken in interpreting the results from relatively small samples sizes, otolith chemical analyses could be useful at these spatial scales to investigate population structure. This information on separate or overlapping populations could be used in future regional fishery management plans.


Subject(s)
Otolithic Membrane , Trace Elements , Animals , Fisheries , Fishes , Otolithic Membrane/chemistry , Trace Elements/analysis
15.
J Sport Rehabil ; 31(8): 1023-1030, 2022 Nov 01.
Article in English | MEDLINE | ID: mdl-35728805

ABSTRACT

CONTEXT: An Optimizing Performance through Intrinsic Motivation and Attention for Learning theory-based motor learning intervention delivering autonomy support and enhanced expectancies (EE) shows promise for reducing cognitive-motor dual-task costs, or the relative difference in primary task performance when completed with and without a secondary cognitive task, that facilitate adaptive injury-resistant movement response. The current pilot study sought to determine the effectiveness of an autonomy support versus an EE-enhanced virtual reality motor learning intervention to reduce dual-task costs during single-leg balance. DESIGN: Within-subjects 3 × 3 trial. METHODS: Twenty-one male and 24 female participants, between the ages of 18 and 30 years, with no history of concussion, vertigo, lower-extremity surgery, or lower-extremity injuries the previous 6 months, were recruited for training sessions on consecutive days. Training consisted of 5 × 8 single-leg squats on each leg, during which all participants mimicked an avatar through virtual reality goggles. The autonomy support group chose an avatar color, and the EE group received positive kinematic biofeedback. Baseline, immediate, and delayed retention testing consisted of single-leg balancing under single- and dual-task conditions. Mixed-model analysis of variances compared dual-task costs for center of pressure velocity and SD between groups on each limb. RESULTS: On the right side, dual-task costs for anterior-posterior center of pressure mean and SD were reduced in the EE group (mean Δ = -51.40, Cohen d = 0.80 and SD Δ = -66.00%, Cohen d = 0.88) compared with the control group (mean Δ = -22.09, Cohen d = 0.33 and SD Δ = -36.10%, Cohen d = 0.68) from baseline to immediate retention. CONCLUSIONS: These findings indicate that EE strategies that can be easily implemented in a clinic or sport setting may be superior to task-irrelevant AS approaches for influencing injury-resistant movement adaptations.


Subject(s)
Biofeedback, Psychology , Psychomotor Performance , Humans , Male , Female , Infant, Newborn , Psychomotor Performance/physiology , Feasibility Studies , Pilot Projects , Task Performance and Analysis
16.
J Biol Chem ; 295(25): 8613-8627, 2020 06 19.
Article in English | MEDLINE | ID: mdl-32393578

ABSTRACT

N-Methyl-d-aspartate type glutamate receptors (NMDARs) are key mediators of synaptic activity-regulated gene transcription in neurons, both during development and in the adult brain. Developmental differences in the glutamate receptor ionotropic NMDA 2 (GluN2) subunit composition of NMDARs determines whether they activate the transcription factor cAMP-responsive element-binding protein 1 (CREB). However, whether the developmentally regulated GluN3A subunit also modulates NMDAR-induced transcription is unknown. Here, using an array of techniques, including quantitative real-time PCR, immunostaining, reporter gene assays, RNA-Seq, and two-photon glutamate uncaging with calcium imaging, we show that knocking down GluN3A in rat hippocampal neurons promotes the inducible transcription of a subset of NMDAR-sensitive genes. We found that this enhancement is mediated by the accumulation of phosphorylated p38 mitogen-activated protein kinase in the nucleus, which drives the activation of the transcription factor myocyte enhancer factor 2C (MEF2C) and promotes the transcription of a subset of synaptic activity-induced genes, including brain-derived neurotrophic factor (Bdnf) and activity-regulated cytoskeleton-associated protein (Arc). Our evidence that GluN3A regulates MEF2C-dependent transcription reveals a novel mechanism by which NMDAR subunit composition confers specificity to the program of synaptic activity-regulated gene transcription in developing neurons.


Subject(s)
Membrane Glycoproteins/metabolism , Neuronal Plasticity/physiology , Transcription, Genetic , Animals , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Calcium/metabolism , Cell Nucleus/metabolism , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Female , Hippocampus/metabolism , MEF2 Transcription Factors/metabolism , Male , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/genetics , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Phosphorylation , RNA Interference , RNA, Small Interfering/metabolism , Rats , Receptors, N-Methyl-D-Aspartate/metabolism , Tetrodotoxin/pharmacology , Transcription, Genetic/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism
17.
J Chem Phys ; 155(11): 114306, 2021 Sep 21.
Article in English | MEDLINE | ID: mdl-34551536

ABSTRACT

This study has examined the relative energetics of nine stationary points associated with the three different radical isomers generated by removing a H atom from ethanol at the O atom (ethoxy, CH3CH2O), the α C atom (CH3CHOH), and the ß C atom (CH2CH2OH). For the first time, CCSD(T) geometry optimizations and harmonic vibrational frequency computations with the cc-pVTZ and aug-cc-pVTZ basis sets have been carried out to characterize two unique minima for each isomer along with three transition state structures with Cs symmetry. Explicitly correlated CCSD(T) computations were also performed to estimate the relative energetics of these nine stationary points near the complete basis set limit. These benchmark results were used to assess the performance of various density functional theory (DFT) and wave function theory methods, and they will help guide method selection for future studies of alcohols and their radicals. The structures generated by abstracting H from the α C atom have significantly lower electronic energies (by at least 7 kcal mol-1) than the CH3CH2O and CH2CH2OH radicals. Although previously reported as a minimum on the ground-state surface, the 2A″ Cs structure of the ethoxy radical was found to be a transition state in this study with MP2, CCSD(T), and a number of DFT methods. An implicit solvation model used in conjunction with DFT and MP2 methods did not qualitatively change the relative energies of the isomers, but the results suggest that the local minima for the CH3CHOH and CH2CH2OH radicals could become more energetically competitive in condensed phase environments, such as liquid water and ethanol.

18.
Regul Toxicol Pharmacol ; 123: 104940, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33964349

ABSTRACT

Systematic reviews (SRs) are common practice in clinical and public health research, but less common in non-human animal research. Systematic reviews of animal studies can be valuable to inform clinical research, to evaluate the need for further animal experiments on a given topic, and to assess the hazard of an environmental exposure in the evaluation of toxicological studies. In the last 10 years, there has been an increase in the number of SRs of animal research, as well as several publications with detailed guidance on how to perform high-quality systematic reviews of experimental animal studies. In order to evaluate current analytical approaches used in SRs of animal studies, easily identify all systematic reviews on a specific topic, and subsequently the original animal studies and their results and promote awareness and understanding of these emerging approaches, we compiled a database of SRs of animal studies. The database was developed using a rigorous, systematic approach and covers a broad range of research fields: preclinical research, toxicology, environmental health, and veterinary medicine. The database currently includes 3113 SRs of animal studies (search date June 2019). In addition to bibliographical information, data on whether or not a risk of bias assessment and meta-analysis were conducted were extracted. For future users, the search features of the database provide users with a platform to identify and select SRs with a particular characteristic for export to Microsoft Word or Microsoft Excel. From there, users may perform additional data extraction to meet their research needs. The database is freely available at www.Mendeley.com (link). The database provides methodologists a comprehensive source that can be used to explore and advance the current methodology applied to SRs of animal studies, and can help researchers to easily identify all systematic reviews on a specific topic, and subsequently the original animal studies and their results and avoid duplication and unnecessary animal research.


Subject(s)
Animals, Laboratory , Databases, Factual , Systematic Reviews as Topic , Animals , Bias , Humans , Public Health
19.
BMC Fam Pract ; 22(1): 31, 2021 02 03.
Article in English | MEDLINE | ID: mdl-33535973

ABSTRACT

BACKGROUND: Interprofessional primary care (IPC) teams provide comprehensive and coordinated care and are ideally equipped to support those populations most at risk of adverse health outcomes during the COVID-19 pandemic, including older adults, and patients with chronic physical and mental health conditions. There has been little focus on the experiences of healthcare teams and no studies have examined IPC practice during the early phase of the COVID-19 pandemic. The objective of the study was to describe the state of interprofessional health provider practice within IPC teams during the COVID-19 pandemic. METHODS: Observational cross-sectional design. A web-based survey was deployed to IPC providers working in team-based primary care clinics in the province of Ontario, Canada. The survey included 26 close-ended and six open-ended questions. Close-ended questions were analyzed using descriptive statistics. Content analysis was used to analyze the open-ended questions. RESULTS: 445 surveys were included in the final analysis. Service delivery shifted from in-person care (77% pre-COVID-19) to telephone (76.5% during the COVID-19 pandemic). Less than half of the respondents (40%) reported receiving any training for virtual delivery. Wait times to access team members were reported to have decreased. There has also been a shift in what IPC providers report as the most commonly seen conditions, with increases in visits related to mental health concerns, acute infections (including COVID-19), social isolation, and resource navigation. Respondents also reported a reduction in healthcare provision for multiple chronic conditions including diabetes, cardiovascular disease, and chronic pain. CONCLUSIONS: IPC teams are rapidly shifting their practice to supporting their patients during the pandemic. A surge in mental health issues has been seen and is expected to continue to increase in response to COVID-19. Understanding early experiences can help plan for future pandemic waves.


Subject(s)
COVID-19/epidemiology , Interprofessional Relations , Primary Health Care/methods , Cross-Sectional Studies , Humans , Mental Disorders/diagnosis , Mental Disorders/epidemiology , Mental Disorders/therapy , Ontario/epidemiology , Patient Care Team/organization & administration , Patient Care Team/statistics & numerical data , Practice Patterns, Physicians'/statistics & numerical data , Primary Health Care/statistics & numerical data , Surveys and Questionnaires
20.
Ecotoxicol Environ Saf ; 208: 111469, 2021 Jan 15.
Article in English | MEDLINE | ID: mdl-33091769

ABSTRACT

Coal ash spills occasionally occur due to the accidental failure of surface impoundments, and toxic metal-laden ash can pose a serious health threat to adjacent aquatic ecosystems. Here, we performed an investigation into longitudinal variations of mercury (Hg) contamination in the Dan River (North Carolina, United States) about 17 and 29 months after a February 2014 coal ash spill incident, in which the reported Hg concentrations in the spilled coal ash (210 ng/g) were 1-2 orders of magnitude higher than the river sediments (2-61 ng/g). We examined total Hg (THg) and methyl Hg (MeHg) in sediments from 0 to 65 km downstream of the spill, and found that most of the variations of THg and MeHg in surface sediments (0-16 cm) could be well accounted by the organic matter content and appeared to be not contaminated by Hg derived from coal ash. In examining MeHg bioaccumulation in invertebrates (aquatic and riparian) and fish in the Dan River and fish in a reservoir downstream of Dan River, we found no evidence of elevated MeHg bioaccumulation due to the 2014 coal ash spill. Thus, we concluded that Hg contamination from the coal ash spill is largely absent in the Dan River for both surface sediments and biota within the first three years of spill (until 2017), even though the majority of coal ash may be buried deeper in the sediment in the river channel and/or the downstream reservoir. Alternatively, the Hg associated with the coal ash is largely not bioavailable for extensive microbial Hg methylation. The findings provide useful insights into remediation strategies for this incident and other coal ash spills.


Subject(s)
Chemical Hazard Release , Coal Ash/analysis , Environmental Monitoring , Mercury/analysis , Water Pollutants, Chemical/analysis , Animals , Ecosystem , Fishes , Methylmercury Compounds/analysis , North Carolina , Rivers , United States , Water Pollutants, Chemical/toxicity
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