Lenacapavir (LEN) is a long-acting, highly potent HIV-1 capsid (CA) inhibitor. The evolution of viral variants under the genetic pressure of LEN identified Q67H, N74D, and Q67H/N74D CA substitutions ...as the main resistance associated mutations (RAMs). Here, we determined high-resolution structures of CA hexamers containing these RAMs in the absence and presence of LEN. Our findings reveal that the Q67H change induces a conformational switch, which adversely affects the inhibitor binding. In the unliganded protein, the His67 side chain adopts the closed conformation by projecting into the inhibitor binding pocket and thereby creating steric hindrance with respect to LEN. Upon the inhibitor binding, the His67 side chain repositions to the open conformation that closely resembles the Gln67 side chain in the WT protein. We propose that the switch from the closed conformation to the open conformation, which is needed to accommodate LEN, accounts for the reduced inhibitor potency with respect to the Q67H CA variant. The N74D CA change results in the loss of a direct hydrogen bond and in induced electrostatic repulsions between CA and LEN. The double Q67H/N74D substitutions exhibited cumulative effects of respective single amino acid changes. An examination of LEN binding kinetics to CA hexamers revealed that Q67H and N74D CA changes adversely influenced the inhibitor binding affinity (
) by primarily affecting the dissociation rate constant (
). We used these structural and mechanistic findings to rationally modify LEN. The resulting analog exhibited increased potency against the Q67H/N74D viral variant. Thus, our studies provide a means for the development of second-generation inhibitors with enhanced barriers to resistance.
LEN is an investigational long-acting agent for future HIV-1 treatment regimens. While ongoing clinical trials have highlighted a largely beneficial profile of LEN for the treatment of HIV-1 infected people with limited therapy options, one notable shortcoming is a relatively low barrier of viral resistance to the inhibitor. Cell culture-based viral breakthrough assays identified N74D, Q67H, and N74D/Q67H capsid changes as the main resistance associated mutations (RAMs). N74D and Q67H capsid substitutions have also emerged in clinical trials in some patients who received subcutaneous LEN. Understanding the structural basis behind viral resistance to LEN is expected to aid in the rational development of improved inhibitors with enhanced barriers to resistance. Here, we report high resolution structures of the main drug resistant capsid variants, which provide mechanistic insight into the viral resistance to LEN. We used these findings to develop an improved inhibitor, which exhibited enhanced activity against the viral Q67H/N74D capsid phenotype compared with that of parental LEN.
The purpose of this study was to examine the relation of different types of negative emotion and regulation and control to 55- to 97-month-olds' internalizing and externalizing problem behaviors. ...Parents and teachers provided information on children's (N = 214) adjustment, dispositional regulation and control, and emotion, and children's regulation was observed during several behavioral tasks. Internalizing was defined in two ways: as social withdrawal (to avoid overlap of items with measures of emotionality) or, more broadly, as anxiety, depression, and psychosomatic complaints. In general, children with externalizing problems, compared with children with internalizing problems and nondisordered children, were more prone to anger, impulsivity, and low regulation. Children with internalizing symptoms were prone to sadness, low attentional regulation, and low impulsivity. Relations between internalizing problems and emotionality were more frequent when the entire internalizing scale was used. Findings suggest that emotion and regulation are associated with adjustment in systematic ways and that there is an important difference between effortful control and less voluntary modes of control.
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Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study examined the concurrent and cross-time relations of parental observed warmth and positive expressivity to children's situational facial and self-reported empathic responding, social ...competence, and externalizing problems in a sample of 180 elementary school children. Data was collected when the children were in second to fifth grades (age: M = 112.8 months), and again 2 years later. Cross-sectional and longitudinal structural equation models supported the hypothesis that parents' (mostly mothers') positive expressivity mediated the relation between parental warmth and children's empathy, and children's empathy mediated the relation between parental positive expressivity and children's social functioning. These relations persisted after controlling for prior levels of parenting and child characteristics. Moreover, concurrent and cross-time consistencies were found on measures of parenting, children's situational empathic responding, and social functioning.
Age changes' measures of prosocial responding and reasoning were examined. Participants' reports of helping, empathy‐related responding, and prosocial moral reasoning were obtained in adolescence ...(from age 15–16 years) and into adulthood (to age 25–26 years). Perspective taking and approval/interpersonal oriented/stereotypic prosocial moral reasoning increased from adolescence into adulthood, whereas personal distress declined. Helping declined and then increased (a cubic trend). Prosocial moral judgment composite scores (and self‐reflective empathic reasoning) generally increased from late adolescence into the early 20s (age 17–18 to 21–22) but either leveled off or declined slightly thereafter (i.e., showed linear and cubic trends); rudimentary needs‐oriented reasoning showed the reverse pattern of change. The increase in self‐reflective empathic moral reasoning was for females only. Thus, perspective taking and some aspects of prosocial moral reasoning—capacities with a strong sociocognitive basis—showed the clearest increases with age, whereas simple prosocial proclivities (i.e., helping, sympathy) did not increase with age.
The relations between mothers' expressed positive and negative emotion and 55-79-month-olds' (76% European American) regulation, social competence, and adjustment were examined. Structural equation ...modeling was used to test the plausibility of the hypothesis that the effects of maternal expression of emotion on children's adjustment and social competence are mediated through children's dispositional regulation. Mothers' expressed emotions were assessed during interactions with their children and with maternal reports of emotions expressed in the family. Children's regulation, externalizing and internalizing problems, and social competence were rated by parents and teachers, and children's persistence was surreptitiously observed. There were unique effects of positive and negative maternal expressed emotion on children's regulation, and the relations of maternal expressed emotion to children's externalizing problem behaviors and social competence were mediated through children's regulation. Alternative models of causation were tested; a child-directed model in which maternal expressivity mediated the effects of child regulation on child outcomes did not fit the data as well.
Prosocial Development in Early Adulthood Eisenberg, Nancy; Guthrie, Ivanna K; Cumberland, Amanda ...
Journal of personality and social psychology,
06/2002, Letnik:
82, Številka:
6
Journal Article
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Consistency of measures of a prosocial personality and prosocial moral judgment over time, and the interrelations among them, were examined. Participants' and friends' reports of prosocial ...characteristics were obtained at ages 21-22, 23-24, and 25-26 years. In addition, participants' prosocial judgment was assessed with interviews and with an objective measure of prosocial moral reasoning at several ages. Reports of prosocial behavior and empathy-related responding in childhood and observations of prosocial behavior in preschool also were obtained. There was interindividual consistency in prosocial dispositions, and prosocial dispositions in adulthood related to empathy/sympathy and prosocial behavior at much younger ages. Interview and objective measures of moral reasoning were substantially interrelated in late adolescence/early adulthood and correlated with participants' and friends' reports of a prosocial disposition.
The purpose of this study was to examine the relations of mothers' and fathers' reported emotion-related practices to parents' and teachers' reports of third-to sixth-grade children's social skills, ...popularity, and coping, as well as the quantity and quality of children's comforting of an infant. Mothers' problem-focused reactions tended to be positively associated with children's social functioning and coping, whereas maternal minimizing reactions tended to be linked to lower levels of social competence and high levels of avoidant coping. There were few findings for fathers' reactions, although fathers reported fewer problem-focused reactions with socially competent, in contrast to less competent, daughters. Emotion-focused and problem-focused maternal reactions, as well as encouragement of the expression of emotion, were associated with boys' children's comforting behavior, although a moderate level of maternal encouragement of the expression of emotion was associated with quality of girls' comforting.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The issue of whether there is consistency in prosocial dispositions was examined with a longitudinal data set extending from ages 4 to 5 years into early adulthood (N = 32). Spontaneous prosocial ...behaviors observed in the preschool classroom predicted actual prosocial behavior, other- and self-reported prosocial behavior, self-reported sympathy, and perspective taking in childhood to early adulthood. Prosocial behaviors that were not expected to reflect an other-orientation (i. e., low cost helping and compliant prosocial behavior) generally did not predict later prosocial behavior or sympathy. Sympathy appeared to partially mediate the relation of early spontaneous sharing to later prosocial dispositions. The results support the view that there are stable individual differences in prosocial responding that have their origins in early childhood.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The purpose of this study was to examine the moderating role of individual differences in negative emotionality in the relations of behavioral and attentional (emotional) regulation to externalizing ...problem behaviors. Teachers' and one parent's reports of children's regulation (attentional and behavioral), emotionality, and problem behavior were obtained when children were in kindergarten to grade 3 and two years later (N = 169; 146 in major analyses); children's behavioral regulation also was assessed with a measure of persistence. According to the best fitting structural equation model, at two ages behavioral dysregulation predicted externalizing behavior problems for children both high and low in negative emotionality, whereas prediction of problem behavior from attentional control was significant only for children prone to negative emotionality. There were unique, additive effects of behavioral and attentional regulation for predicting problem behavior as well as moderating effects of negative emotionality for attentional regulation.
Relations between self-reported parental reactions to children's negative emotions (PNRs) and children's socially appropriate/problem behavior and negative emotionality were examined longitudinally. ...Evidence was consistent with the conclusion that relations between children's externalizing (but not internalizing) emotion and parental punitive reactions to children's negative emotions are bidirectional. Reports of PNRs generally were correlated with low quality of social functioning. In structural models, mother-reported problem behavior at ages 10-12 was at least marginally predicted from mother-reported problem behavior, children's regulation, and parental punitive or distress reactions. Moreover, parental distress and punitive reactions at ages 6-8 predicted reports of children's regulation at ages 8-10, and regulation predicted parental punitive reactions at ages 10-12. Father reports of problem behavior at ages 10-12 were predicted by earlier problem behavior and parental distress or punitive reactions; some of the relations between regulation and parental reactions were similar to those in the models for mother-reported problem behavior. Parental perceptions of their reactions were substantially correlated over 6 years. Some nonsupportive reactions declined in the early to mid-school years, but all increased into late childhood/early adolescence.
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