Neural crest cells (NCCs) are migratory, multipotent embryonic cells that are unique to vertebrates and form an array of clade-defining adult features. The evolution of NCCs has been linked to ...various genomic events, including the evolution of new gene-regulatory networks
, the de novo evolution of genes
and the proliferation of paralogous genes during genome-wide duplication events
. However, conclusive functional evidence linking new and/or duplicated genes to NCC evolution is lacking. Endothelin ligands (Edns) and endothelin receptors (Ednrs) are unique to vertebrates
, and regulate multiple aspects of NCC development in jawed vertebrates
. Here, to test whether the evolution of Edn signalling was a driver of NCC evolution, we used CRISPR-Cas9 mutagenesis
to disrupt edn, ednr and dlx genes in the sea lamprey, Petromyzon marinus. Lampreys are jawless fishes that last shared a common ancestor with modern jawed vertebrates around 500 million years ago
. Thus, comparisons between lampreys and gnathostomes can identify deeply conserved and evolutionarily flexible features of vertebrate development. Using the frog Xenopus laevis to expand gnathostome phylogenetic representation and facilitate side-by-side analyses, we identify ancient and lineage-specific roles for Edn signalling. These findings suggest that Edn signalling was activated in NCCs before duplication of the vertebrate genome. Then, after one or more genome-wide duplications in the vertebrate stem, paralogous Edn pathways functionally diverged, resulting in NCC subpopulations with different Edn signalling requirements. We posit that this new developmental modularity facilitated the independent evolution of NCC derivatives in stem vertebrates. Consistent with this, differences in Edn pathway targets are associated with differences in the oropharyngeal skeleton and autonomic nervous system of lampreys and modern gnathostomes. In summary, our work provides functional genetic evidence linking the origin and duplication of new vertebrate genes with the stepwise evolution of a defining vertebrate novelty.
Depression in patients with cardiovascular disease is independently associated with progression of heart disease, major adverse cardiac events, and mortality. A wide variety of depression treatment ...strategies have been studied in randomized controlled trials as the field works to identify optimal depression treatments in this population. A contemporary scoping review of the literature can help to consolidate and synthesize the growing and disparate literature on depression treatment trials in people with cardiovascular disease. We conducted a scoping review utilizing a systematic search of the literature via 4 databases (PubMed, PsycINFO, EMBASE, and Google Scholar) from database inception to March 2020. We identified 42 relevant randomized controlled trials of depression treatment interventions in patients with cardiac disease (n=9181 patients with coronary artery disease, n=1981 patients with heart failure). Selective serotonin reuptake inhibitors appear to be safe in patients with cardiac disease and to have beneficial effects on depression (and some suggestion of cardiac benefit) in patients with coronary artery disease, with less evidence of their efficacy in heart failure. In contrast, psychotherapy appears to be effective for depression in coronary artery disease and heart failure, but with less evidence of cardiac benefit. Newer multimodal depression care management approaches that utilize flexible approaches to patients' care have been less studied but appear promising across cardiac patient groups. Selective serotonin reuptake inhibitors may be preferred in the treatment of patients with coronary artery disease, psychotherapy may be preferred in heart failure, and more flexible depression care management approaches have shown promise by potentially using both approaches based on patient needs.
The evolutionary origin of the autopod involved a loss of the fin-fold and associated dermal skeleton with a concomitant elaboration of the distal endoskeleton to form a wrist and digits. ...Developmental studies, primarily from teleosts and amniotes, suggest a model for appendage evolution in which a delay in the AER-to-fin-fold conversion fuelled endoskeletal expansion by prolonging the function of AER-mediated regulatory networks. Here, we characterize aspects of paired fin development in the paddlefish Polyodon spathula (a non-teleost actinopterygian) and catshark Scyliorhinus canicula (chondrichthyan) to explore aspects of this model in a broader phylogenetic context. Our data demonstrate that in basal gnathostomes, the autopod marker HoxA13 co-localizes with the dermoskeleton component And1 to mark the position of the fin-fold, supporting recent work demonstrating a role for HoxA13 in zebrafish fin ray development. Additionally, we show that in paddlefish, the proximal fin and fin-fold mesenchyme share a common mesodermal origin, and that components of the Shh/LIM/Gremlin/Fgf transcriptional network critical to limb bud outgrowth and patterning are expressed in the fin-fold with a profile similar to that of tetrapods. Together these data draw contrast with hypotheses of AER heterochrony and suggest that limb-specific morphologies arose through evolutionary changes in the differentiation outcome of conserved early distal patterning compartments.
The role of Homeobox transcription factors during fin and limb development have been the focus of recent work investigating the evolutionary origin of limb-specific morphologies. Here we characterize ...the expression of HoxD genes, as well as the cluster-associated genes Evx2 and LNP, in the paddlefish Polyodon spathula, a basal ray-finned fish. Our results demonstrate a collinear pattern of nesting in early fin buds that includes HoxD14, a gene previously thought to be isolated from global Hox regulation. We also show that in both Polyodon and the catshark Scyliorhinus canicula (a representative chondrichthyan) late phase HoxD transcripts are present in cells of the fin-fold and co-localize with And1, a component of the dermal skeleton. These new data support an ancestral role for HoxD genes in patterning the fin-folds of jawed vertebrates, and fuel new hypotheses about the evolution of cluster regulation and the potential downstream differentiation outcomes of distinct HoxD-regulated compartments.
The identification of clinical candidate LY3522348 (compound 23) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). ...Optimization began with highly efficient (S)-2-(2-methylazetidin-1-yl)-6-(1H-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile (3). Efforts focused on developing absorption, distribution, metabolism, potency, and in vitro safety profiles to support oral QD dosing in patients. Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials.
BackgroundN-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac ventricular wall stress that is incorporated into pulmonary hypertension (PH) risk stratification models. ...Sendaway sampling may enable patients to perform NT-proBNP tests remotely. This UK-wide study aimed to assess the agreement of sendaway NT-proBNP with standard venous NT-proBNP and to assess the effect of delayed processing.MethodsReference venous NT-proBNP was collected from PH patients. Samples for capillary and venous sendaway tests were collected contemporaneously, mailed to a reference laboratory and processed at 3 and 7 days using a Roche Cobas e411 device. Differences in paired measurements were analysed with Passing-Bablok regression, percentage difference plots and the % difference in risk strata.Results113 patients were included in the study. 13% of day 3 capillary samples were insufficient. Day 3 capillary samples were not equivalent to reference samples (Passing Bablok analysis slope of 0.91 (95% CI 0.88 to 0.93) and intercept of 6.0 (95% CI 0.2 to 15.9)). The relative median difference was −7% and there were acceptable limits of agreement. Day 3 capillary NT-proBNP accurately risk stratified patients in 93.5% of cases. By comparison, day 3 venous results accurately risk stratified patients in 90.1% of cases and were equivalent by Passing-Bablok regression. Delayed sampling of sendaway tests led to an unacceptable level of agreement and systematically underestimated NT-proBNP.ConclusionsSendaway NT-proBNP sampling may provide an objective measure of right ventricular strain for virtual PH clinics. Results must be interpreted with caution in cases of delayed sampling.
Precise phenotypic characterization of prenatal tobacco exposure (PTE)–related disruptive behavior (DB) that integrates nuanced measures of both exposures and outcomes is optimal for elucidating ...underlying mechanisms. Using this approach, our goals were to identify dimensions of DB most sensitive to PTE prior to school entry and assess contextual variation in these dimensions.
A community obstetric sample of N = 369 women (79.2% lifetime smokers; 70.2% pregnancy smokers) from two Midwestern cities were assessed for PTE using cotinine-calibrated interview-based reports at 16, 28, and 40 weeks of gestation. A subset of n = 244 who completed observational assessments with their 5-year-old children in a subsequent preschool follow-up study constitute the analytic sample. Using two developmentally-meaningful dimensions previously associated with emergent clinical risk for DB—irritability and noncompliance—we assessed children with 2 parent-report scales: the Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB) and the Early Childhood Inventory (ECI). We also assessed children by direct observation across 3 interactional contexts with the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS). We used generalized linear models to examine between-child variability across behavioral dimensions, and mixed effects models to examine directly observed within-child variability by interactional context.
Increasing PTE predicted increasing impairment in preschoolers' modulation of negative affect (irritability), but not negative behavior (noncompliance) across reported (MAP-DB) and observed (DB-DOS) dimensional measures. Moreover, children's PTE-related irritability was more pronounced when observed with parents than with the examiner. The ECI did not detect PTE-related irritability nor noncompliance.
Nuanced, dimension- and context-specific characterization of PTE-related DB described can optimize early identification of at-risk children.
•Understanding mechanisms linking prenatal tobacco exposure (PTE) with disruptive behavior (DB) requires improved measures.•We combined bioassay-corrected PTE with developmentally sensitive, context-sensitive DB assessment.•PTE showed a dose-dependent association with preschoolers’ irritability in parent, but not examiner contexts.•PTE-related effects were not detected by a commonly used symptom-based measure.•Nuanced, developmentally informed, context-sensitive measures are critical to the clear specification of PTE’s effects.•Nuanced, developmentally informed and context-sensitive measures are critical to the clear specification of PTE’s effects.
Maternal smoking during pregnancy (MSDP) has been robustly associated with externalizing problems and their developmental precursors in offspring in studies using behavioral teratologic designs ...(Wakschlag et al., Am J Public Health 92(6):966–974,
2002
; Espy et al., Dev Psychol 47(1):153–169,
2011
). In contrast, the use of behavior genetic approaches has shown that the effects commonly attributed to MSDP can be explained by family-level variables (D’Onofrio et al., Dev Psychopathol 20(01):139–164,
2008
). Reconciling these conflicting findings requires integration of these study designs. We utilize longitudinal data on a preschool proband and his/her sibling from the Midwest Infant Development Study-Preschool (MIDS-P) to test for teratologic and family level effects of MSDP. We find considerable variation in prenatal smoking patterns both within and across pregnancies within families, indicating that binary smoking measures are not sufficiently capturing exposure. Structural equation models indicate that both conduct disorder and oppositional defiant disorder symptoms showed unique effects of MSDP over and above family level effects. Blending high quality exposure measurement with a within-family design suggests that it is premature to foreclose the possibility of a teratologic effect of MSDP on externalizing problems. Implications and recommendations for future studies are discussed.
While the majority of pregnant smokers do not respond to intervention, little is known about how a subset of pregnant smokers known as spontaneous quitters achieve sustained biologically-confirmed ...abstinence through delivery in the absence of intervention. We explore a developmental framework to address this question by viewing spontaneous quitting as an adaptive parenting behavior, facilitated by abilities necessary for sensitive parenting, or responsiveness. Utilizing existing data, we examined responsiveness from parenting assessments in women who exhibited a variety of smoking patterns during pregnancy, including spontaneous quitting.
Participants were N = 305 pregnant women assessed for smoking prospectively and biochemically at 16 weeks, 28 weeks, delivery, and 4 weeks postpartum, then reassessed with their children 5 years later with directly-observed home- and lab-based measures of parenting. We used linear regression analysis to compare spontaneous quitters with women who exhibited other prenatal smoking patterns on parenting responsiveness, controlling for potential confounders.
In home-based observations, spontaneous quitters (n = 22) exhibited greater responsiveness with their children relative to intermittent pregnancy smokers n = 70; β = 0.258, p = .022; persistent pregnancy smokers n = 66; β = 0.228, p = .040; former smokers (quit before pregnancy) n = 78; β = 266, p = .028; and never smokers n = 69; β = 0.312, p = .009. Hypothesized differences were not observed in lab-based and self-report measures.
Putative protective characteristics in spontaneous quitters were captured in mother-child interactions at home, but not in lab-based and maternal report measures of responsiveness. Specification of these characteristics using prospective designs that oversample for spontaneous quitters is recommended to enable translation to preventive interventions.
•Most pregnant smokers who have not quit on their own do not quit with intervention.•Smokers who quit on their own early in pregnancy are understudied.•Spontaneous quitters may possess unmeasured protective factors beyond lower risks.•Quitters were more responsive to their children at home compared to other women.•Quitters were more responsive even compared to women who never smoked.
•Prenatal smoking patterns may reflect differences in maternal empathic capacity.•Relation between face processing and prenatal smoking depended on genetic context.•Enhancing empathy may improve ...prenatal smoking cessation for selected individuals.•Oxytocin functioning may be a biological substrate in prenatal smoking behavior.
Prenatal smoking cessation has been described as an empathic action “for the baby,” but this has not been empirically demonstrated. We capitalized on a genetically-characterized extant dataset with outstanding measurement of prenatal smoking patterns and maternal face processing data (as an indicator of empathy) to test this hypothesis, and explore how empathy and smoking patterns may be moderated by a genetic substrate of empathy, the oxytocin receptor gene (OXTR). Participants were 143Caucasian women from the East Boston family study with repeated prospective reports of smoking level, adjusted based on repeated cotinine bioassays. Salivary DNA and face processing (Diagnostic Analysis of Nonverbal Accuracy-2) were assessed 14 years later at an adolescent follow-up of offspring. Two-thirds of participants reported smoking prior to pregnancy recognition. Of these, 21% quit during pregnancy; 56% reduced smoking, and 22% smoked persistently at the same level. A significant interaction between face processing and OXTR variants previously associated with increased sensitivity to social context, rs53576GG and rs2254298A, was found (β=−.181; p=.015); greater ability to identify distress in others was associated with lower levels of smoking during pregnancy for rs53576(GG)/rs2254298(A) individuals (p=.013), but not for other genotypes (p=.892). Testing this “empathy hypothesis of prenatal smoking cessation” in larger studies designed to examine this question can elucidate whether interventions to enhance empathy can improve prenatal smoking cessation rates.
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