A Monoclonal Antibody for Malaria Prevention.

BACKGROUND: Additional interventions are needed to reduce the morbidity and mortality caused by malaria. METHODS: We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS. RESULTS: A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 µg per milliliter at the time of controlled human malaria infection. CONCLUSIONS: Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).

The Impact of Prenatal Alcohol Exposure on Longitudinal Growth, Nutritional Status, and Insulin-Like Growth Factor 1 in Early Childhood in Leyte, the Philippines.

OBJECTIVE: To assess the impact and potential mechanistic pathways of prenatal alcohol exposure (PAE) on longitudinal growth and nutritional status in early childhood. STUDY DESIGN: A cohort of 296 mother-infant dyads (32% with PAE vs 68% unexposed) were recruited in Leyte, the Philippines, and followed from early gestation through 24 months of age. PAE was assessed using serum phosphatidylethanol (PEth) captured twice prenatally and in cord blood and supplemented with self-reported alcohol consumption. Linear mixed models were used to examine longitudinal effects of PAE on growth from birth through 2 years including key potential mediating factors (placental histopathology, and infant serum leptin and Insulin-like Growth Factor 1 [IGF-1]). RESULTS: After adjusting for potential confounders, we found that PAE was significantly associated with a delayed blunting of linear growth trajectories (height-for-age z-score, body length) and weight (weight-for-age z-score, body weight) that manifested between 4 and 6 months and continued through 12-24 months. PAE was also associated with a decreased rate of mid-upper-arm circumference growth from birth to 12 months, and a lower mean IGF-1 levels at birth and 6 months. CONCLUSION: This study demonstrates a delayed impact of PAE on growth that manifested around 6 months of age, underscoring the importance of routine clinical monitoring in early childhood. Furthermore, the findings supported prior animal model findings that suggest a mechanistic role for IGF-1 in PAE-induced growth delay.

Early-life matters: The role of fetal adrenal steroids in the relationship between cytokines within the placental circulation and cognitive development among infants in the Philippines.

Prenatal exposure to inflammation is related to the risk for cognitive impairment in offspring. However, mechanisms underlying the link between inflammatory cytokines at the maternal-fetal interface and human cognitive development are largely unknown. This study addressed this research gap by examining whether i) cytokines within the placenta are associated with different domains of neurocognitive development during infancy, and ii) if DHEA-S in cord blood mediates these associations. We also explored the role of early-life socioeconomic status (SES) in moderating the effect of fetal adrenal steroids on cognitive development in low- and middle-income country contexts. A cohort of 242 mother-infant dyads in Leyte, the Philippines participated in the study and all of them were followed from early pregnancy until 12-months. Concentrations of pro- and anti-inflammatory cytokines in the placenta, and DHEA-S in cord blood collected at delivery were evaluated. The multifactorial aspects of the infant's cognitive functioning were assessed based on the Bayley Scales of Infant Development, third edition (BSID-III). We used Structural Equation Modelling (SEM) with an orthogonal rotation to examine associated paths among latent variables of pro- and anti-inflammatory cytokines in the placenta, fetal neuroendocrine factors, and cognitive development. Pathway analyses showed that both pro- and anti-inflammatory cytokines in the placenta were indirectly related to cognitive (p < 0.05) and language developmental outcomes (p < 0.1) via DHEA-S in cord blood among the low SES group. Yet, we found no statistically significant indirect effect of pro- or anti-inflammatory cytokines on neurocognitive development among the high SES sub-sample. This study extends our understanding of how early-life socioeconomic conditions modify biological pathways underlying the relationship between prenatal factors and postpartum cognitive development.

Evaluating Measures of Externalizing Personality Pathology Traits in Black and White American Adolescents in a Program for at-Risk Youths.

Adolescent personality assessment measures can aid in the identification of traits that are associated with various types of maladjustment. Externalizing personality pathology traits (e.g., antisocial, borderline, and narcissistic personality disorder features) are particularly relevant for many problematic outcomes, yet measures that assess these traits have not been validated extensively in diverse samples. The present study aimed to examine the properties of measures of externalizing personality pathology traits in a sample of White (n = 184) and Black (n = 99) adolescents participating in a residential program for at-risk youth. The fit of the proposed structure for these measures was tested in the sample as a whole and in each racial group separately. Associations between these measures and the count of disciplinary infractions received while in the program were also tested. Measures were found to have less than optimal fit in this sample, especially among Black adolescents. Suggestions for future research and clinical use of these measures are discussed.

Impaired Intrauterine Growth in the Context of Maternal Hookworm Infection During Gestation.

Hookworm infection is associated with poor nutritional outcomes, anemia, and impaired cognitive performance. We examined the association between maternal hookworm infection and birth outcomes in a cohort of women in Leyte, Philippines. We observed poor intrauterine growth characteristics associated with maternal hookworm only among male offspring, with lower birth weight, head circumference, and placental surface area. Male neonates also had higher insulin-like growth factor 2 (IGF-2) and lower adiponectin in cord blood. These data intriguingly suggest nutritional impacts of maternal hookworm infection during pregnancy may be divergent based on sex of the offspring.

Interspecies chimeric conditions affect the developmental rate of human pluripotent stem cells.

Human pluripotent stem cells hold significant promise for regenerative medicine. However, long differentiation protocols and immature characteristics of stem cell-derived cell types remain challenges to the development of many therapeutic applications. In contrast to the slow differentiation of human stem cells in vitro that mirrors a nine-month gestation period, mouse stem cells develop according to a much faster three-week gestation timeline. Here, we tested if co-differentiation with mouse pluripotent stem cells could accelerate the differentiation speed of human embryonic stem cells. Following a six-week RNA-sequencing time course of neural differentiation, we identified 929 human genes that were upregulated earlier and 535 genes that exhibited earlier peaked expression profiles in chimeric cell cultures than in human cell cultures alone. Genes with accelerated upregulation were significantly enriched in Gene Ontology terms associated with neurogenesis, neuron differentiation and maturation, and synapse signaling. Moreover, chimeric mixed samples correlated with in utero human embryonic samples earlier than human cells alone, and acceleration was dose-dependent on human-mouse co-culture ratios. The altered gene expression patterns and developmental rates described in this report have implications for accelerating human stem cell differentiation and the use of interspecies chimeric embryos in developing human organs for transplantation.

Understanding At-Risk Youths: Average PAI-A Scores and Their Associations with Impulsivity-Related Constructs.

The purpose of this study was to extend research on the Personality Assessment Inventory-Adolescent (PAI-A; Morey, 2007) to include an examination of mean PAI-A results and associations between the PAI-A and indicators of impulsivity in a large sample of at-risk adolescents (Mage = 16.75; 79% male; 64% Caucasian) in a military-style residential program. Included in this study are archival records for a diverse sample of 497 youths who participated in the program during a 2-year period. Average T scores on PAI-A scales ranged from 44.67 to 65.41. Moderate to large positive associations (rs = .30-.65) were found between relevant PAI-A scales and both UPPS-P scales and self-reported substance use. There were smaller effects (r = .17) for associations between the PAI-A and program disciplinary infractions. Small to large group differences (ds = .19-.93) on PAI-A scales differentiated youths who had experience with arrests or NSSI from those who did not. This study provides information about the under-studied but vulnerable youths occupying the space between the normative population and youths with identified clinical or legal problems. It also clarifies how impulsivity and impulsivity-related behaviors may be represented on the PAI-A.

The Validity of the Personality Assessment Inventory-Adolescent in Assessing Callous-Unemotional Traits in At-Risk Adolescents.

This study examines the validity of the Personality Assessment Inventory-Adolescent (PAI-A; Morey) in assessing callous-unemotional (CU) traits within two independent samples of at-risk adolescents from a residential intervention program. The study tests the extent to which CU traits are represented within PAI-A scales with respect to empirically- or theoretically-related indicators, such as antisociality, aggression, low warmth, low social connectedness, and subdued internalizing psychopathology. The PAI-A substantive scales statistically accounted for an average of 55.0% of the variance in total scores on the Inventory of Callous-Unemotional Traits (ICU; Frick) across samples. Broadly, PAI-A substantive scales evinced theoretically-consistent relations with CU traits. Consistent with expectations, CU traits were broadly related to PAI-A-assessed constructs of antisocial features, aggression, low warmth and social disconnection, but not to subdued internalizing symptoms. Moreover, some of the PAI-A clinical, treatment consideration, and interpersonal scales or subscales demonstrated differential relations across the traits. Implications for assessment of CU traits using the PAI framework are discussed. Overall, this research adds to the literature on CU traits in broadband personality assessment and provides a foundation for future research on CU traits using the PAI-A.

Automated minute scale RNA-seq of pluripotent stem cell differentiation reveals early divergence of human and mouse gene expression kinetics.

Pluripotent stem cells retain the developmental timing of their species of origin in vitro, an observation that suggests the existence of a cell-intrinsic developmental clock, yet the nature and machinery of the clock remain a mystery. We hypothesize that one possible component may lie in species-specific differences in the kinetics of transcriptional responses to differentiation signals. Using a liquid-handling robot, mouse and human pluripotent stem cells were exposed to identical neural differentiation conditions and sampled for RNA-sequencing at high frequency, every 4 or 10 minutes, for the first 10 hours of differentiation to test for differences in transcriptomic response rates. The majority of initial transcriptional responses occurred within a rapid window in the first minutes of differentiation for both human and mouse stem cells. Despite similarly early onsets of gene expression changes, we observed shortened and condensed gene expression patterns in mouse pluripotent stem cells compared to protracted trends in human pluripotent stem cells. Moreover, the speed at which individual genes were upregulated, as measured by the slopes of gene expression changes over time, was significantly faster in mouse compared to human cells. These results suggest that downstream transcriptomic response kinetics to signaling cues are faster in mouse versus human cells, and may offer a partial account for the vast differences in developmental rates across species.

Longitudinal associations of callous-unemotional and oppositional defiant behaviors over a three-year interval for Spanish children.

The objective was to determine the longitudinal associations between callous-unemotional (CU) and oppositional defiant (OD) behaviors from the first to fourth grades for Spanish children. Four possible outcomes were evaluated: (a) CU behaviors in the first grade predict increases in OD behaviors in the fourth grade, controlling for OD behaviors in the first grade; (b) OD behaviors in the first grade predict increases in CU behaviors in the fourth grade, controlling for CU behaviors in the first grade; (c) both unique effects are significant; and (d) neither unique effect is significant. A longitudinal panel model with two latent variables (CU and OD behaviors), three sources (mothers, fathers, teachers), and two occasions (spring of the first and fourth grades) was used to evaluate the four possibilities among 758 (54% boys) first grade and 469 (53% boys) fourth grade Spanish children. For mother-, father-, and teacher-reports, OD behaviors in the first grade predicted increases in CU behaviors in the fourth grade, after controlling for CU behaviors in the first grade, whereas CU behaviors in the first grade did not predict increases in OD behaviors in the fourth grade, after controlling for OD behaviors in the first grade. OD behaviors thus conferred independent vulnerability to increases in CU behaviors 3 years later among young children.

Internalizing problems and their impact on the relation between callous-unemotional traits, narcissism, and aggression.

Narcissism and callous-unemotional (CU) traits have demonstrated relations with youth aggression across studies. However, different forms of narcissism and internalizing problems may exacerbate the relation between CU traits and aggression. To that end, the current study examined the degree to which interactions among internalizing problems, CU traits, and dimensions of narcissism related to aggression in a sample of 219 adolescents (83.1% males), ages 16-19, enrolled in a military-style residential program. Consistent with previous research, psychopathy-linked narcissism significantly moderated the relation between CU traits and aggression. Addtionally, self-reported aggression was highest among adolescents who endorsed high levels of CU traits, psychopathy-linked narcissism, and internalizing problems. The same pattern of results was not evident for other forms of narcissism. These results suggest that internalizing problems further increase the probability of aggression among adolescents with psychopathic tendencies (i.e., CU traits, psychopathy-linked narcissism). Further implications are discussed.

Species-specific developmental timing is maintained by pluripotent stem cells ex utero.

How species-specific developmental timing is controlled is largely unknown. By following human embryonic stem (ES) cell and mouse epiblast stem (EpiS) cell differentiation through detailed RNA-sequencing time courses, here we show that pluripotent stem cells closely retain in vivo species-specific developmental timing in vitro. In identical neural differentiation conditions in vitro, gene expression profiles are accelerated in mouse EpiS cells compared to human ES cells with relative rates of differentiation closely reflecting the rates of progression through the Carnegie stages in utero. Dynamic Time Warping analysis identified 3389 genes that were regulated more quickly in mouse EpiS cells and identified none that were regulated more quickly in human ES cells. Interestingly, we also find that human ES cells differentiated in teratomas maintain the same rate of differentiation observed in vitro in spite of being grown in a mouse host. These results suggest the existence of a cell autonomous, species-specific developmental clock that pluripotent stem cells maintain even out of context of an intact embryo.

The Arctic in the Twenty-First Century: Changing Biogeochemical Linkages across a Paraglacial Landscape of Greenland.

The Kangerlussuaq area of southwest Greenland encompasses diverse ecological, geomorphic, and climate gradients that function over a range of spatial and temporal scales. Ecosystems range from the microbial communities on the ice sheet and moisture-stressed terrestrial vegetation (and their associated herbivores) to freshwater and oligosaline lakes. These ecosystems are linked by a dynamic glacio-fluvial-aeolian geomorphic system that transports water, geological material, organic carbon and nutrients from the glacier surface to adjacent terrestrial and aquatic systems. This paraglacial system is now subject to substantial change because of rapid regional warming since 2000. Here, we describe changes in the eco- and geomorphic systems at a range of timescales and explore rapid future change in the links that integrate these systems. We highlight the importance of cross-system subsidies at the landscape scale and, importantly, how these might change in the near future as the Arctic is expected to continue to warm.

Adolescent Communal Narcissism and Peer Perceptions.

OBJECTIVE: The present study extended recent work on communal narcissism to a sample of at-risk adolescents. Although narcissism is widely considered an agentic personality construct, Gebauer and colleagues (Gebauer, Sedikides, Verplanken, & Maio, 2012) demonstrated the existence and utility of a communal narcissism construct in adults. The extent to which this variant of narcissism applies to adolescents is not yet known. Because communal narcissism (e.g., feeling that one is the most helpful, is a great influence on others, will bring about world peace) may actually be aversive to others, we investigated the associated self- and peer perceptions of adolescent communal narcissism. METHOD: Participants were 136 adolescents (104 males, 32 females; 52.2% White, 42.2% Black, 5.6% Other) aged 16-19, who were attending a 22-week residential program together. Participants completed self-report measures of narcissism and interpersonal behavior, as well as a peer nomination procedure. RESULTS: Self-reported communal narcissism was significantly related to self-reported pro-social behavior but was associated with peer-reported aggression, similar to the findings for nonpathological narcissism, which is considered agentic. CONCLUSIONS: Adolescent communal narcissism appears to be tied to negative peer perceptions. The implications for understanding the interpersonal consequences of adolescent grandiosity in communal domains are discussed.

How do different dimensions of adolescent narcissism impact the relation between callous-unemotional traits and self-reported aggression?

The current study examined the moderating influence that different aspects of narcissism have on the relation between callous-unemotional (CU) traits and aggression in a sample of 720 adolescents (500 males), ages 16-19 enrolled in a 22-week residential program. Findings from the two studies revealed that psychopathy-linked narcissism as assessed by the Antisocial Process Screening Device (APSD; Frick & Hare, 2001; Antisocial process screening device. Toronto: Multi-Health Systems.) and vulnerable narcissism as assessed using the Pathological Narcissism Inventory (PNI; Pincus et al., 2009; Initial construction and validation of the Pathological Narcissism Inventory. Psychological Assessment, 21, 365-379) significantly moderated the relation between CU traits and aggression in adolescents. Conversely, non-pathological narcissism assessed by the Narcissistic Personality Inventory for Children (NPIC; Barry, Frick, & Killian, 2003; The relation of narcissism and self-esteem to conduct problems in children. Journal of Clinical Child and Adolescent Psychology, 32, 139-152) and PNI grandiose narcissism did not significantly impact this relation. These results suggest that forms of narcissism most closely connected to internalizing problems combined with CU traits are associated with relatively heightened aggression in youth. The implications of these findings are discussed. Aggr. Behav. 43:14-25, 2017. © 2016 Wiley Periodicals, Inc.

Adolescent social media use and mental health from adolescent and parent perspectives.

This study investigated adolescent and parent reports of adolescent social media use and its relation to adolescent psychosocial adjustment. The sample consisted of 226 participants (113 parent-adolescent dyads) from throughout the United States, with adolescents (55 males, 51 females, 7 unreported) ranging from ages 14 to 17. Parent and adolescent reports of the number of adolescents' social media accounts were moderately correlated with parent-reported DSM-5 symptoms of inattention, hyperactivity/impulsivity, ODD, anxiety, and depressive symptoms, as well as adolescent-reported fear of missing out (FoMO) and loneliness. Lastly, anxiety and depressive symptoms were highest among adolescents with a relatively high number of parent-reported social media accounts and relatively high FoMO. The implications of these findings and need for related longitudinal studies are discussed.

Adolescent Narcissism, Aggression, and Prosocial Behavior: The Relevance of Socially Desirable Responding.

An important threat to validity in personality research pertains to an individual's motivation to respond in a socially desirable manner on self-report inventories. This issue was examined in this study in the context of narcissism, aggression, and prosocial behavior in a sample of at-risk adolescents. Participants were 161 adolescents (128 males, 29 females, 4 not reported) ranging in age from 16 to 19 years who were attending a residential program for youth who have dropped out of school. Overall, socially desirable response tendencies were negatively correlated with vulnerable narcissism and self-reported aggression. Moreover, low socially desirable responses strengthened the relation between narcissism and self-reported aggression. Socially desirable responding was not associated with self- or peer-reported prosocial behavior and did not moderate the relation between narcissism and prosocial behavior. These findings indicate that the relation between narcissism and aggression is attenuated by concerns with social desirability. However, further work is needed in broader samples of adolescents to more closely examine whether social desirability concerns actually mitigate aggression among some youth or signify underreporting of one's problem behaviors.

Gonadal steroids and body composition, strength, and sexual function in men.

BACKGROUND: Current approaches to diagnosing testosterone deficiency do not consider the physiological consequences of various testosterone levels or whether deficiencies of testosterone, estradiol, or both account for clinical manifestations. METHODS: We provided 198 healthy men 20 to 50 years of age with goserelin acetate (to suppress endogenous testosterone and estradiol) and randomly assigned them to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily for 16 weeks. Another 202 healthy men received goserelin acetate, placebo gel or testosterone gel, and anastrozole (to suppress the conversion of testosterone to estradiol). Changes in the percentage of body fat and in lean mass were the primary outcomes. Subcutaneous- and intraabdominal-fat areas, thigh-muscle area and strength, and sexual function were also assessed. RESULTS: The percentage of body fat increased in groups receiving placebo or 1.25 g or 2.5 g of testosterone daily without anastrozole (mean testosterone level, 44±13 ng per deciliter, 191±78 ng per deciliter, and 337±173 ng per deciliter, respectively). Lean mass and thigh-muscle area decreased in men receiving placebo and in those receiving 1.25 g of testosterone daily without anastrozole. Leg-press strength fell only with placebo administration. In general, sexual desire declined as the testosterone dose was reduced. CONCLUSIONS: The amount of testosterone required to maintain lean mass, fat mass, strength, and sexual function varied widely in men. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; estrogen deficiency primarily accounted for increases in body fat; and both contributed to the decline in sexual function. Our findings support changes in the approach to evaluation and management of hypogonadism in men. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00114114.).

MicroRNA-494 is a master epigenetic regulator of multiple invasion-suppressor microRNAs by targeting ten eleven translocation 1 in invasive human hepatocellular carcinoma tumors.

UNLABELLED: Vascular invasion provides a direct route for tumor metastasis. The degree to which microRNA (miRNA) expression plays a role in tumor vascular invasion is unclear. Here, we report that miR-494 is up-regulated in human hepatocellular carcinoma (HCC) tumors with vascular invasion and can promote HCC cell invasiveness by gene inactivation of multiple invasion-suppressor miRNAs. Our results show that ten eleven translocation (TET) methylcytosine dioxygenase, predominantly TET1 in HCC cells, is a direct target of miR-494. The reduced 5'-hydroxymethylcytosine levels observed in the proximal cytosine-phosphate-guanine (CpG) regions of multiple invasion-suppressor miRNA genes are strongly associated with their transcriptional repression upon miR-494 overexpression, whereas enforced DNA demethylation can abolish the repression. Furthermore, TET1 knockdown shows a similar effect as miR-494 overexpression. Conversely, miR-494 inhibition or enforced TET1 expression is able to restore invasion-suppressor miRNAs and inhibit miR-494-mediated HCC cell invasion. CONCLUSIONS: miR-494 can trigger gene silencing of multiple invasion-suppressor miRNAs by inhibiting genomic DNA demethylation by direct targeting of TET1, thereby leading to tumor vascular invasion.

Callous-unemotional traits and empathy deficits: Mediating effects of affective perspective-taking and facial emotion recognition.

Although empathy deficits are thought to be associated with callous-unemotional (CU) traits, findings remain equivocal and little is known about what specific abilities may underlie these purported deficits. Affective perspective-taking (APT) and facial emotion recognition may be implicated, given their independent associations with both empathy and CU traits. The current study examined how CU traits relate to cognitive and affective empathy and whether APT and facial emotion recognition mediate these relations. Participants were 103 adolescents (70 males) aged 16-18 attending a residential programme. CU traits were negatively associated with cognitive and affective empathy to a similar degree. The association between CU traits and affective empathy was partially mediated by APT. Results suggest that assessing mechanisms that may underlie empathic deficits, such as perspective-taking, may be important for youth with CU traits and may inform targets of intervention.