Parental Scaffolding Research Articles

Synthesis, Microtubule-Binding Affinity, and Antiproliferative Activity of New Epothilone Analogs and of an EGFR-Targeted Epothilone-Peptide Conjugate.

A new simplified, epoxide-free epothilone analog was prepared incorporating an N-(2-hydroxyethyl)-benzimidazole side chain, which binds to microtubules with high affinity and inhibits cancer cell growth in vitro with nM potency. Building on this scaffold, a disulfide-linked conjugate with the purported EGFR-binding (EGFR, epidermal growth factor receptor) peptide GE11 was then prepared. The conjugate retained significant microtubule-binding affinity, in spite of the size of the peptide attached to the benzimidazole side chain. The antiproliferative activity of the conjugate was significantly lower than for the parent scaffold and, surprisingly, was independent of the EGFR expression status of cells. Our data indicate that the disulfide-based conjugation with the GE11 peptide is not a viable approach for effective tumor-targeting of highly potent epothilones and probably not for other cytotoxics.

Locked-Azobenzene: Testing the Scope of a Unique Photoswitchable Scaffold for Cell Physiology.

Azobenzenes are the most widely studied photoswitches, and have become popular optical probes for biological systems. The cis configuration is normally metastable, meaning the trans configuration is always thermodynamically favored. The unique exception to this rule is an azobenzene having a two-carbon bridge between ortho positions, substitutions that lock the photoswitch in its cis configuration. Only thoroughly chemically characterized relatively recently, we describe the first applications of this locked-azobenzene (or "LAB") scaffold with two derivatives designed to control ion flow in pyramidal neurons in acutely isolated brain slices. Our LAB derivatives maintain most of the desirable photochemical properties of the parent scaffold, and work as designed in living cells. However, LAB derivitization changes the trans photostationary state from >85% of the parent photoswitch to about 50%, suggesting that careful design considerations must be given for future applications of the LAB scaffold in biological areas.

Conceptual design of hybrid PCSK9 lead inhibitors against coronary artery disease

Abstract The enzyme, Proprotein Convertase Subtilisin Kexin type-9 (PCSK 9) inhibition serves as a significant target to prevent the risk of Coronary Artery Disease. Hence, this work is focused on the exploration of novel PCSK 9 lead inhibitors through In silico approach. In abidance to the study, BREED algorithm has been taken to design novel hybridised ligands. Subsequently, various in silico screening studies were performed in Biovia Discovery Studio 2017. Novel ligand generation protocol generated 595 hybridised ligands from the 51 parent scaffolds. These ligands were mapped and screened by ludi interactions of the active site PCSK 9 and were reduced to 245 hit compounds. The docking studies showed that the berberine skeleton contained molecule possessed CDOCKER energy (−13.5582 Kcal/mol) and formed strong interactions with Arg93, Arg97 and His137 residues. The developed pharmacophore model revealed that hydrogen bond acceptor and negative ionizable charges are necessary for the inhibition of PCSK 9. The mapping of pharmacophore model confirmed that 96 molecules were as best fit. Finally, toxicity and dynamic simulation studies confirmed that safe and stable complex formation between lead molecules and PCSK 9 receptor. The results concluded that the 15 lead molecules are proved as potent and safe PCSK9 inhibitors.

Intrinsic and Extrinsic Predictors of Emotion Regulation in Children with Autism Spectrum Disorder.

Difficulties regulating emotion have been linked to comorbid psychopathology in children with autism spectrum disorder (ASD), but little empirical work has examined predictors of dysregulation in this population. Forty-six families of children with ASD participated in a laboratory visit that included direct measurement of children's IQ, ASD symptoms, and psychophysiological reactivity. Child emotion regulation was observed during independent and co-regulatory tasks, and parental scaffolding was rated in the dyadic context. ASD symptom severity emerged as the strongest predictor of child emotion dysregulation across contexts. Child age and parental scaffolding also uniquely predicted child dysregulation in the dyadic task. Implications for conceptualizing intrinsic and extrinsic influences on emergent emotion regulation in children with ASD are discussed, as are applications to intervention.

RNA-binding protein trinucleotide repeat-containing 6A regulates the formation of circular RNA circ0006916, with important functions in lung cancer cells.

Circular RNAs (circRNAs) are widespread and diverse endogenous RNAs distinct from traditional linear RNAs, which may regulate gene expression in eukaryotes. However, the function of human circRNAs, including their potential role in lung cancer, remains largely unknown. We screened the circRNA circ0006916, which was evidently down-regulated in 16HBE-T cells (anti-benzopyrene-trans-7, 8-dihydrodiol-9, 10-epoxide-transformed human bronchial epithelial cells), and in A549 and H460 cell lines. Silencing of circ0006916, but not its parental gene homer scaffolding protein 1 (HOMER1), promoted cell proliferation via speeding up the cell cycle process rather than by inhibiting apoptosis; conversely, overexpression of circ0006916 had the opposite effect. Luciferase-screening assay indicated that circ0006916 bound to miR-522-3p and inhibited pleckstrin homology domain and leucine rich repeat protein phosphatase 1 (PHLPP1) activity. We also explored the effect of the RNA-binding protein trinucleotide repeat-containing 6A (TNRC6A) on circ0006916 production. Circ0006916 expression was decreased after silencing TNRC6A. TNRC6A bound to the intron regions around the circRNA-forming exons of circ0006916, as shown by RNA immunoprecipitation assay combined with sequencing analysis. The association of circ0006916 with TNRC6A was further verified by RNA pull-down assays. We then constructed a carrier and confirmed that TNRC6A binding to the flanked intron region of circ0006916 was necessary for generation of circ0006916. These results demonstrate that TNRC6A regulates the biogenesis of the circRNA circ0006916, which has a regulatory role in cell growth.

Culture-specific links between maternal executive function, parenting, and preschool children's executive function in South Korea.

Research on the relationships between parental factors and children's executive function (EF) has been conducted mainly in Western cultures. This study provides the first empirical test, in a non-Western context, of how maternal EF and parenting behaviours relate to child EF. South Korean mothers and their preschool children (N=95 dyads) completed EF tasks. Two aspects of parental scaffolding were observed during a puzzle task: contingency (i.e., adjusting among levels of scaffolding according to the child's ongoing evidence of understanding) and intrusiveness (i.e., directive, mother-centred interactions). Maternal EF and maternal contingency each accounted for unique variance in child EF, above and beyond child age, child language and maternal education. Maternal intrusiveness, however, was not significantly related to child EF. Additionally, no mediating role of parenting was found in the maternal and child EF link. However, child language was found to partially mediate the link between maternal contingency and child EF. These results complement prior findings by revealing distinctive patterns in the link between maternal EF, parenting behaviours, and child EF in the Korean context.

Characterization of a Novel Series of D4 Dopamine Receptor Ligands Reveals Structure‐Activity Relationships for Selective Partial Agonists

D4 dopamine receptors (D4R) are G protein‐coupled receptors that play important roles in cognition, attention, and decision making. D4R ligands have been shown to alter cognition and behavior in animal models of drug addiction and variations in the DRD4 gene have been associated with novelty‐seeking and risk behavior, as well as ADHD. A better understanding of D4R‐mediated signaling is essential to understanding and treating D4R‐associated disorders, including substance abuse disorders. Despite its clinical implications, there are currently few compounds that selectively modulate the D4R receptor. Such compounds are important to study D4R function and identify favorable pharmacology for disease treatment. We created a small next‐generation compound library using computational modelling to design D4R ligands based on the parental scaffold of the prototypical D4R partial agonist A‐412997. This library was analyzed for D2R, D3R, and D4R activity using both agonist and antagonist radioligand competition binding assays and functional signaling readouts (β‐arrestin recruitment and cAMP inhibition). We found that substitutions on the piperidine and pyridine moieties, as well as modifications in linker length, led to several novel lead compounds with improved selectivity and potency, and varying degrees of agonist efficacy. Compounds were identified that displayed high binding affinity (<100 nM) for the D4R coupled with a >1000‐fold selectivity vs. the D3R and D2R. Importantly, these ligands displayed a range of agonist efficacies from highly efficacious partial agonists to full antagonists of the D4R. Interestingly, some compounds with similar binding affinities showed divergent functional efficacies, allowing for the generation of a preliminary structure‐activity relationship underlying functional efficacy. Further optimization may allow for directed tuning of functional efficacy that, when coupled to in vivo behavioral studies, may provide insight into the importance of relative efficacy levels as a means to treat D4R‐related disorders.Support or Funding InformationNINDS IRPThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Parental executive function and verbal ability matter for scaffolding.

Despite the importance of parental scaffolding for later child cognitive outcomes and academic achievement, sources of individual variation in scaffolding are not fully understood. Scaffolding places extensive demands on cognitive capacity, including planning, flexibly shifting, and inhibition. Executive function (EF) is therefore a parental cognitive ability especially important for effective scaffolding. In this study, parents and preschool-aged children completed a challenging puzzle to assess scaffolding. EF and verbal ability were measured for parents and children. Parental verbal ability was used as an index of global higher-order cognitive function. Higher levels of parental EF related to more effective scaffolding, above and beyond parental verbal ability and independent of child cognitive level. These results highlight the significance of considering parental cognitive capacities in future studies to better understand the sources of individual differences in scaffolding. (PsycINFO Database Record

Training of parental scaffolding in high-socio-economic status families: How do parents of full- and preterm-born toddlers benefit?

Preterm children have an increased risk regarding self-regulation development. Given the strong link between parenting behaviour (i.e., scaffolding and sensitivity) and children's self-regulation, parental training presents a promising way to counteract the negative consequences of preterm birth. We explored the effectiveness of parental training by comparing a basic scaffolding training and a combined scaffolding/sensitivity training to an active treatment-control group (stress management). Basic and combined treatments should increase parents' domain-specific self-efficacy (DSSE) and beliefs on parental co-regulation and the promotion of learning (BCL) more than the control treatment should. No such differences were expected for parents' domain-general self-efficacy (DGSE). We examined whether parents of preterm and full-term children benefitted equally from training conditions. A total of 87 parents of full-term and 35 parents of preterm toddlers (24-36months of age, corrected for prematurity) participated. Based on a quasi-experimental pre-test-post-test follow-up design, parents were randomly assigned to treatments. A multimethod approach was applied, including self-report, parent-child interactions, and standardized behavioural tasks. The presented study is limited to questionnaire data on parents' DGSE, DSSE, and BCL. An overall increase resulted from pre- to post-test and/or follow-up. Parents' BCL changed significantly stronger in the combined training than in the control group. Parents of preterm and full-term children benefitted equally from basic and combined training. The combined training enhanced BCL among parents of full-term and preterm children the most. If such training also yields improvement on the behavioural level, this finding will advance preterm aftercare.

Scaffolding for motivation by parents, and child homework motivations and emotions: Effects of a training programme.

Based on the principles of scaffolding for motivation and on the assumptions of self-determination theory, two studies aimed to assess the role played by perceived parental autonomy-supportive scaffolding on child homework autonomous motivation, self-efficacy, affect, and engagement. The results of Study 1, which involved 122 parents and their children, showed that the higher the parental autonomous motivation, the more their children perceived them as autonomy-supportive while scaffolding for motivation, and hence developed autonomous motivation, self-efficacy, and engagement in homework. In Study 2, 37 parents were involved in a four-session training programme that focused on sustaining autonomy-supportive scaffolding modalities. The training decreased parental negative affect, prevented child negative affect increase, and maintained child homework motivation. The discussion focuses on the strength that parents have with regard to helping their children develop less negative, and potentially also more positive attitude towards homework, through autonomy support as a scaffold for motivation.

Noscapine Derivatives as New Chiral Catalysts in Asymmetric Synthesis­: Highly Enantioselective Addition of Diethylzinc to Aldehydes­

Noscapine, a natural alkaloid, has never been used as a parent scaffold in chiral induction. The first examples of noscapinoid compounds as efficient catalysts in asymmetric synthesis are now reported. Three derivatives of noscapine were synthesized from its reaction with different Grignard reagents. Asymmetric addition of diethylzinc to aldehydes­ was performed in the presence of these catalysts in high yields and good to excellent ees.

Parenting matters: Moderation of biological and community risk for obesity

Contributions of parental limit setting, negativity, scaffolding, warmth, and responsiveness to Body Mass Index (BMI) were examined. Parenting behaviors were observed in parent-child interactions, and child BMI was assessed at 5 years of age. Mothers provided demographic information and obtained child saliva samples used to derive cortisol concentration indicators (N = 250). Geospatial crime indices were computed based on publically available information for a subsample residing within the boundaries of a Pacific Northwest city (N = 114). Maternal warmth and limit setting moderated the association between child HPA-axis regulation and BMI. BMI was higher for children at lower cortisol concentrations with greater maternal warmth and lower for youngsters with mid-range cortisol values under high maternal limit setting. Maternal scaffolding moderated the effects of crime exposure, so that lower scaffolding translated into higher child BMI with greater neighborhood crime exposure. These parenting behaviors could be leveraged in obesity prevention/intervention efforts.

Exploration of the 150 cavity and the role of serendipity in the discovery of inhibitors of influenza virus A neuraminidase

Influenza pandemics are an ongoing threat for the human population, as the avian influenza viruses H5N1 and H7N9 continue to circulate in the bird population and the chance of avian to human transmission increases. Neuraminidase, a glycoprotein located on the surface of the influenza virus, plays a crucial role in the viral replication process and, hence, has proven to be a useful target enzyme for the treatment of influenza infections. The discovery that certain subtypes of influenza neuraminidase have an additional cavity, the 150 cavity, near the substrate binding site has triggered considerable interest in the design of influenza inhibitors that exploit this feature. Currently available antiviral drugs, neuraminidase inhibitors oseltamivir and zanamivir, were designed using crystal structures predating this discovery by some years. This mini review is aimed at summarizing our group’s efforts, together with related work from other groups, on neuraminidase inhibitors that are designed to exploit both the catalytic site and the 150 cavity. The design of a parent scaffold that yields a potent inhibitor that is active in cell culture assays and retains activity against several neuraminidases from mutant strains is also described. Finally, the role of serendipity in the discovery of a new class of potent neuraminidase inhibitors with a novel spirolactam scaffold is also highlighted.

Parental contributors to children’s persistence and school readiness

This study examined whether parental teaching strategies (e.g., scaffolding) are predictive of school readiness competencies through children’s task persistence, and if the strength of the relation varies across two contextual features of parenting (e.g., warmth and harsh discipline). Past research has examined contextual features of parenting or specific parenting practices as being related to children’s achievement, with less attention given to how they might interact. In the present study, a moderated-mediation model was tested to assess whether parental scaffolding skills predict children’s language-cognitive and social–emotional school readiness, mediated by children’s persistence and moderated by parent warmth and harsh discipline. Exploratory analyses assessed whether a competing sequential-mediation model better explained the associations among parenting, children’s persistence, and school readiness than a moderated-mediation model. In a low-income sample of families from the Early Head Start Research and Evaluation Project (N = 2977), parental scaffolding significantly predicted children’s persistence at 36 months, as well as both latent constructs of school readiness before kindergarten. Persistence partially mediated the link between parental scaffolding and both latent constructs of school readiness. Neither warmth nor harsh discipline moderated the mediational model. In the sequential-mediation model, parent scaffolding and children’s persistence mediated the associations between warmth and harsh discipline and both latent constructs of school readiness. The sequential-mediation model provided a similar fit to the data as the moderated-mediation model. The results indicate that parental scaffolding can promote children’s persistence and later school readiness.

Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2).

Neurodegenerative diseases share certain pathophysiological hallmarks that represent common targets for drug discovery. In particular, dysfunction of proteostasis and the resultant apoptotic death of neurons represent common pathways for pharmacological intervention. A library of aromatic carbamate derivatives based on the clinically available drug flupirtine was synthesized to determine a structure-activity relationship for neuroprotective activity. Several derivatives were identified that possess greater protective effect in human induced pluripotent stem cell-derived neurons, protecting up to 80% of neurons against etoposide-induced apoptosis at concentrations as low as 100 nM. The developed aromatic carbamates possess physicochemical properties desirable for CNS therapeutics. The primary known mechanisms of action of the parent scaffold are not responsible for the observed neuroprotective activity. Herein, we demonstrate that neuroprotective aromatic carbamates function to increase the Bcl-2/Bax ratio to an antiapoptotic state and activate autophagy through induction of beclin 1.

Parental Scaffolding in Mathematics Homework Among Malaysian Private Preschoolers: a Case Study

The study aims to have a better understanding on the parental scaffolding in mathematics homework among preschoolers in the Malaysian context. This is achieved by exploring to what extent Malaysian parents provide scaffolding to their preschoolers in mathematics homework interactions. Investigations about the strategies employed by the parents during scaffolding and non-scaffolding interactions were carried out. Three mothers, with different parenting styles and education levels, and their preschoolers were observed and interviewed. In general, the occurrences of contingency, fading and transfer of responsibility were found to be scarce. Diagnostic and intervention strategies were also analysed and discussed.

For Better or for Worse? Positive and Negative Parental Influences on Young Children's Executive Function.

Despite rapidly growing research on parental influences on children's executive function (EF), the uniqueness and specificity of parental predictors and links between adult EF and parenting remain unexamined. This 13-month longitudinal study of 117 parent-child dyads (60 boys; Mage at Time 1=3.94years, SD=0.53) included detailed observational coding of parent-child interactions and assessed adult and child EF and child verbal ability (VA). Supporting a differentiated view of parental influence, negative parent-child interactions and parental scaffolding showed unique and specific associations with child EF, whereas the home learning environment and parental language measures showed global associations with children's EF and VA.

Imidazo[1,2-α]pyridines possess adenosine A1 receptor affinity for the potential treatment of cognition in neurological disorders

Previous research has shown that bicyclic 6:5-fused heteroaromatic compounds with two N-atoms have variable degrees of adenosine A1 receptor antagonistic activity. Prompted by this imidazo[1,2-α]pyridine analogues were synthesized and evaluated for their adenosine A1 and A2A receptor affinity via radioligand binding studies and subjected to a GTP shift assay to determine its adenosine A1 receptor agonistic or antagonistic functionality. Imidazo[1,2-α]pyridine, the parent scaffold, was found devoid of affinity for the adenosine A1 and A2A receptors. The influence of substitution on position C2 showed no improvement for either adenosine A1 or A2A receptor affinity. The addition of an amino or a cyclohexylamino group to position C3 also showed no improvement of adenosine A1 or A2A receptor affinity. Surprisingly para-substitution on the phenyl ring at position C2 in combination with a cyclohexylamino group at position C3 led to adenosine A1 receptor affinity in the low micromolar range with compound 4d showing: (1) the highest affinity for the adenosine A1 receptor with a Ki value of 2.06µM and (2) adenosine A1 receptor antagonistic properties. This pilot study concludes that para-substituted 3-cyclohexylamino-2-phenyl-imidazo[1,2-α]pyridine analogues represent an interesting scaffold to investigate further structure-activity relationships in the design of novel imidazo[1,2-α]pyridine-based adenosine A1 receptor antagonists for the treatment of neurodegenerative disorders.

Sympathetic Under-Arousal and Externalizing Behavior Problems in Children with Autism Spectrum Disorder.

Children with autism spectrum disorder (ASD) commonly exhibit co-occurring externalizing behavior problems, which can impede learning opportunities and contribute significantly to caregiver stress. Substantial theory and research has linked under-arousal of the sympathetic nervous system to increased externalizing problems in children without ASD, but under-arousal has not been considered as an explanatory mechanism for individual differences among children with ASD. We tested the notion that lower electrodermal activity (EDA) would predict more externalizing problems in children with ASD, and considered the degree to which parent co-regulatory support could buffer this risk. Forty children with ASD between the ages of 4 and 11years and their primary caregivers participated in a laboratory visit that included various play, compliance, and problem-solving regulatory tasks. EDA was measured through wireless wrist sensors, parental scaffolding was observed during a dyadic problem-solving task, and parents rated their children's externalizing behavior problems. As predicted, low EDA during the compliance-oriented tasks directly predicted higher child externalizing problems. Parental scaffolding moderated the link between under-arousal during the problem-solving regulatory tasks and externalizing problems such that the relation was observed in the context of low, but not high, support. Implications for relevant theories (e.g., fearlessness theory, stimulation-seeking theory) are discussed, and the potential for psychophysiological patterns to inform intervention with these children is considered.

Review Article: Various Biological Activities of Coumarin and Oxadiazole Derivatives.

In this review article data is collected regarding the various derivatives of coumarin and oxadiazole as both these have wide range of biological activities and they can be further modified to synthesize more effective and potent drugs. Coumarin class of organic compounds consists of 1,2-benzopyrone ring system as a basic parent scaffold. These benzopyrones are subdivided into alpha-benzopyrones and gamma benzopyrones; with coumarin class of compounds belonging to alpha-benzopyrones. Since the last few years, coumarins were synthesized in many of their derivative forms. Their pharmacological, therapeutic and biochemical properties depend upon their pattern of substitution. Coumarins exhibit a wide range of pharmacological activities, which includes anti-diabetic, anti-viral, anti-microbial, anticancer, anti-oxidant, anti-parasitic, anti-helminthic, anti-proliferative, anti-convulsant, anti-inflammatory and antihypertensive activities. 1,3,4-Oxadiazole is a heterocyclic compound containing an oxygen atom and two nitrogen atoms in a five-membered ring. It is derived from furan by substitution of two methylene groups (=CH) with two pyridine type nitrogens (-N=). There are three known isomers: 1,2,4-oxadiazole, 1,2,3-oxadiazole and 1,2,5- oxadiazole. Oxadiazole moiety shows antimicrobial, anticancer and anti-inflammatory activity and suitably substituted 1,3,4-oxadiazole having biological activities like antimicrobial, anticancer and other biological activities.