Parental Distress and Parenting Behavior in Families of Preschool Children with and Without ASD: Spillover and Buffering.

Parents of children with autism spectrum disorder (ASD) report increased distress relative to parents of children with neurotypical development. Parent well-being is generally considered a key determinant of parenting behavior, thus increased distress may spill over into less optimal parenting in families of children with ASD. However, evidence is mixed regarding the degree to which parenting is actually compromised in this population, suggesting the possibility of buffering, wherein the parenting of children with ASD may be robust against spillover from increased parental distress. The current study tested competing spillover and buffering models with regard to relations among child ASD status, parental distress, and parenting behavior. Parents of preschoolers with (n = 73) and without (n = 55) ASD completed self-report measures of parenting stress, depressive symptoms, and emotion dysregulation, as well as of positive and negative parenting behaviors. Families of preschoolers with ASD reported higher distress and negative parenting, and lower positive parenting than did their counterparts. Findings supported the spillover model for negative parenting such that increased parental distress accounted for status-group differences in negative parenting. In contrast, potential buffering was observed for positive parenting in that an inverse association between distress and parenting was observed for parents of children with neurotypical development only. Findings highlight the potential benefit of intervention to reduce parental distress in families of children with ASD, but also suggest some existing ability of these families to buffer certain parenting behaviors from deleterious effects of parent distress.

Sibling Support and Perceived Daily Hassles in Latino and Non-Latino Families of Children with DD.

Parents of children with developmental delay (DD) report significantly higher levels of parenting stress compared to parents of children with typical development. There is a heightened need for social support among families of children with DD. Siblings play an important role in these contexts as a supportive resource and primary stress buffer. Little to no research has examined how these stress and supportive processes may differ among Latino and non-Latino parents. The current study examined the relation between sibling support and parents' perceived daily hassles between Latino and non-Latino parents of children with DD (N = 146; 65% Latino; mean parent age = 37.39 years; mean child age = 49.63 months; SD = 7.9). Latinos reported significantly greater use of sibling support and lower perceived daily hassles compared to non-Latino counterparts. In the combined sample, greater sibling support was significantly correlated with lower daily hassles. When examined separately in Latino and non-Latino groups, this correlation only remained significant among Latinos. The interaction between ethnicity and sibling support on perceived daily hassles was approaching significance, such that Latinos who reported high levels of sibling support reported lower perceived daily hassles. Findings emphasize the universal importance of familial support systems for the well-being of parents of children with DD and point to the possible protective role of Latino cultural factors that influence the degree to which these supports are employed. Results may inform culturally sensitive adaptations to parenting interventions for Latino families that harness sibling support to target and buffer parenting stress.

Feasibility and acceptability of a whole-school social-marketing intervention to prevent unintended teenage pregnancies and promote sexual health: evidence for progression from a pilot to a phase III randomised trial in English secondary schools.

BACKGROUND: Reducing unintended teenage pregnancy and promoting adolescent sexual health remains a priority in England. Both whole-school and social-marketing interventions are promising approaches to addressing these aims. However, such interventions have not been rigorously trialled in the UK and it is unclear if they are appropriate for delivery in English secondary schools. We developed and pilot trialled Positive Choices, a new whole-school social marketing intervention to address unintended teenage pregnancy and promote sexual health. Our aim was to assess the feasibility and acceptability of the intervention and trial methods in English secondary schools against pre-defined progression criteria (relating to randomisation, survey follow-up, intervention fidelity and acceptability and linkage to birth/abortion records) prior to carrying out a phase III trial of effectiveness and cost-effectiveness. METHODS: Pilot RCT with integral process evaluation involving four intervention and two control schools in south-east England. The intervention comprised a student needs survey; a student/staff-led school health promotion council; a classroom curriculum for year-9 students (aged 13-14); whole-school student-led social-marketing activities; parent information; and a review of local and school-based sexual health services. Baseline surveys were conducted with year 8 (aged 12-13) in June 2018. Follow-up surveys were completed 12 months later. Process evaluation data included audio recording of staff training, surveys of trained staff, staff log books and researcher observations of intervention activities. Survey data from female students were linked to records of births and abortions to assess the feasibility of these constituting a phase III primary outcome. RESULTS: All six schools were successfully randomised and retained in the trial. Response rates to the survey were above 80% in both arms at both baseline and follow-up. With the exception of the parent materials, the fidelity target for implementation of essential elements in three out of four schools was achieved. Student surveys indicated 80% acceptability among those who reported awareness of the programme and interviews with staff suggested strong acceptability. Linkage to birth/abortion records was feasible although none occurred among participants. CONCLUSIONS: The criteria for progression to a phase III trial were met. Our data suggest that a whole-school social-marketing approach may be appropriate for topics that are clearly prioritised by schools. A phase III trial of this intervention is now warranted to establish effectiveness and cost-effectiveness. Births and terminations are not an appropriate primary outcome measure for such a trial. TRIAL REGISTRATION: ISRCTN65324176.

Pairing automated mark-recapture and social network models to explore the effects of landscape configuration on hummingbird foraging patterns.

Landscape changes can alter pollinator movement and foraging patterns which can in turn influence the demographic processes of plant populations. We leveraged social network models and four fixed arrays of five hummingbird feeders equipped with radio frequency identification (RFID) data loggers to study rufous hummingbird (Selasphorus rufus) foraging patterns in a heterogeneous landscape. Using a space-for-time approach, we asked whether forest encroachment on alpine meadows could restrict hummingbird foraging movements and impede resource discovery. We fit social network models to data on 2221 movements between feeders made by 29 hummingbirds. Movements were made primarily by females, likely due to male territoriality and early migration dates. Distance was the driving factor in determining the rate of movements among feeders. The posterior mean effects of forest landscape variables (local canopy cover and intervening forest cover) were negative, but with considerable uncertainty. Finally, we found strong reciprocity in hummingbird movements, indicative of frequent out and back movements between resources. Together, these findings suggest that reciprocal movements by female hummingbirds could help maintain bidirectional gene flow among nearby subpopulations of ornithophilous plants; however, if the distance among meadows increases with further forest encroachment, this may limit foraging among progressively isolated meadows.

Epifluorescence-based three-dimensional traction force microscopy.

We introduce a novel method to compute three-dimensional (3D) displacements and both in-plane and out-of-plane tractions on nominally planar transparent materials using standard epifluorescence microscopy. Despite the importance of out-of-plane components to fully understanding cell behavior, epifluorescence images are generally not used for 3D traction force microscopy (TFM) experiments due to limitations in spatial resolution and measuring out-of-plane motion. To extend an epifluorescence-based technique to 3D, we employ a topology-based single particle tracking algorithm to reconstruct high spatial-frequency 3D motion fields from densely seeded single-particle layer images. Using an open-source finite element (FE) based solver, we then compute the 3D full-field stress and strain and surface traction fields. We demonstrate this technique by measuring tractions generated by both single human neutrophils and multicellular monolayers of Madin-Darby canine kidney cells, highlighting its acuity in reconstructing both individual and collective cellular tractions. In summary, this represents a new, easily accessible method for calculating fully three-dimensional displacement and 3D surface tractions at high spatial frequency from epifluorescence images. We released and support the complete technique as a free and open-source code package.

Etched ion tracks in amorphous SiO2 characterized by small angle x-ray scattering: influence of ion energy and etching conditions.

Small angle x-ray scattering was used to study the morphology of conical structures formed in thin films of amorphous SiO2. Samples were irradiated with 1.1 GeV Au ions at the GSI UNILAC in Darmstadt, Germany, and with 185, 89 and 54 MeV Au ions at the Heavy Ion Accelerator Facility at ANU in Canberra, Australia. The irradiated material was subsequently etched in HF using two different etchant concentrations over a series of etch times to reveal conically shaped etched channels of various sizes. Synchrotron based SAXS measurements were used to characterize both the radial and axial ion track etch rates with unprecedented precision. The results show that the ion energy has a significant effect on the morphology of the etched channels, and that at short etch times resulting in very small cones, the increased etching rate of the damaged region in the radial direction with respect to the ion trajectory is significant.

Increased Alcohol-Drinking Induced by Manipulations of mGlu5 Phosphorylation within the Bed Nucleus of the Stria Terminalis.

The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress, and glutamate transmission within this region has been implicated in the neurobiology of alcoholism. Herein, we used a combination of immunoblotting, neuropharmacological and transgenic procedures to investigate the role for metabotropic glutamate receptor 5 (mGlu5) signaling within the BNST in excessive drinking. We discovered that mGlu5 signaling in the BNST is linked to excessive alcohol consumption in a manner distinct from behavioral or neuropharmacological endophenotypes that have been previously implicated as triggers for heavy drinking. Our studies demonstrate that, in male mice, a history of chronic binge alcohol-drinking elevates BNST levels of the mGlu5-scaffolding protein Homer2 and activated extracellular signal-regulated kinase (ERK) in an adaptive response to limit alcohol consumption. Male and female transgenic mice expressing a point mutation of mGlu5 that cannot be phosphorylated by ERK exhibit excessive alcohol-drinking, despite greater behavioral signs of alcohol intoxication and reduced anxiety, and are insensitive to local manipulations of signaling in the BNST. These transgenic mice also show selective insensitivity to alcohol-aversion and increased novelty-seeking, which may be relevant to excessive drinking. Further, the insensitivity to alcohol-aversion exhibited by male mice can be mimicked by the local inhibition of ERK signaling within the BNST. Our findings elucidate a novel mGluR5-linked signaling state within BNST that plays a central and unanticipated role in excessive alcohol consumption.SIGNIFICANCE STATEMENT The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress and alcohol, and glutamate transmission within BNST is implicated in the neurobiology of alcoholism. The present study provides evidence that a history of excessive alcohol drinking increases signaling through the metabotropic glutamate receptor 5 (mGlu5) receptor within the BNST in an adaptive response to limit alcohol consumption. In particular, disruption of mGlu5 phosphorylation by extracellular signal-regulated kinase within this brain region induces excessive alcohol-drinking, which reflects a selective insensitivity to the aversive properties of alcohol intoxication. These data indicate that a specific signaling state of mGlu5 within BNST plays a central and unanticipated role in excessive alcohol consumption.

Creation of forest edges has a global impact on forest vertebrates.

Forest edges influence more than half of the world's forests and contribute to worldwide declines in biodiversity and ecosystem functions. However, predicting these declines is challenging in heterogeneous fragmented landscapes. Here we assembled a global dataset on species responses to fragmentation and developed a statistical approach for quantifying edge impacts in heterogeneous landscapes to quantify edge-determined changes in abundance of 1,673 vertebrate species. We show that the abundances of 85% of species are affected, either positively or negatively, by forest edges. Species that live in the centre of the forest (forest core), that were more likely to be listed as threatened by the International Union for Conservation of Nature (IUCN), reached peak abundances only at sites farther than 200-400 m from sharp high-contrast forest edges. Smaller-bodied amphibians, larger reptiles and medium-sized non-volant mammals experienced a larger reduction in suitable habitat than other forest-core species. Our results highlight the pervasive ability of forest edges to restructure ecological communities on a global scale.

Adolescent Mice Are Resilient to Alcohol Withdrawal-Induced Anxiety and Changes in Indices of Glutamate Function within the Nucleus Accumbens.

Binge-drinking is the most prevalent form of alcohol abuse and while an early life history of binge-drinking is a significant risk factor for subsequent alcoholism and co-morbid affective disorders, relatively little is known regarding the biobehavioral impact of binge-drinking during the sensitive neurodevelopmental period of adolescence. In adult mice, a month-long history of binge-drinking elicits a hyper-glutamatergic state within the nucleus accumbens (Acb), coinciding with hyper-anxiety. Herein, we employed a murine model of binge-drinking to determine whether or not: (1) withdrawal-induced changes in brain and behavior differ between adult and adolescent bingers; and (2) increased behavioral signs of negative affect and changes in Acb expression of glutamate-related proteins would be apparent in adult mice with less chronic binge-drinking experience (14 days, approximating the duration of mouse adolescence). Adult and adolescent male C57BL/6J mice were subjected to a 14-day binge-drinking protocol (5, 10, 20 and 40% alcohol (v/v) for 2 h/day), while age-matched controls received water. At 24 h withdrawal, half of the animals from each group were assayed for negative affect, while tissue was sampled from the shell (AcbSh) and core (AcbC) subregions of the remaining mice for immunoblotting analyses. Adult bingers exhibited hyper-anxiety when tested for defensive marble burying. Additionally, adult bingers showed increased mGlu1, mGlu5, and GluN2b expression in the AcbSh and PKCε and CAMKII in the AcbC. Compared to adults, adolescent mice exhibited higher alcohol intake and blood alcohol concentrations (BACs); however, adolescent bingers did not show increased anxiety in the marble-burying test. Furthermore, adolescent bingers also failed to exhibit the same alcohol-induced changes in mGlu and kinase protein expression seen in the adult bingers. Irrespective of age, bingers exhibited behavioral hyperactivity in the forced swim test (FST) compared to water drinkers, which was paralleled by an increase in AcbC levels of GluN2b. Thus, a 2-week period of binge-drinking is sufficient to produce a hyper-anxious state and related increases in protein indices of Acb glutamate function. In contrast, adolescents were resilient to many of the effects of early alcohol withdrawal and this attenuated sensitivity to the negative consequences of binge drinking may facilitate greater alcohol intake in adolescent drinkers.

Binge alcohol drinking elicits persistent negative affect in mice.

Cessation from chronic alcohol abuse often produces a dysphoric state that can persist into protracted withdrawal. This dysphoric state is theorized to function as a negative reinforcer that maintains excessive alcohol consumption and/or precipitates relapse in those struggling to abstain from alcohol. However, we know relatively little regarding the impact of cessation from binge drinking on behavioral measures of negative affect and related neurobiology. Male C57BL/6J mice were given access to unsweetened 20% alcohol for 6 weeks under modified Drinking-in-the-dark procedures, followed by behavioral testing beginning either 1 or 21 days into withdrawal. Mice were administered a behavioral test battery consisting of: the elevated plus maze, light/dark box, novel object test, marble burying test, Porsolt forced swim test and sucrose preference test to assess anxiogenic and depressive signs. Egr1 immunostaining was used to quantify cellular activity within the central nucleus of the amygdala (CEA), basolateral amygdala (BLA), bed nucleus of the stria terminalis (BNST), and the nucleus accumbens (Acb) shell (AcbSh) and core (AcbC). Compared to water controls, alcohol-drinking mice exhibited higher indices of emotionality in the majority of behavioral assays. The hyper-emotionality exhibited by binge drinking mice was apparent at both withdrawal time-points and correlated with higher Egr1+ cell counts in the CEA and BNST, compared to controls. These data show that affective symptoms emerge very early after cessation of binge drinking and persist into protracted withdrawal. A history of binge drinking is capable of producing enduring neuroadaptations within brain circuits mediating emotional arousal.

Prioritizing therapeutic targets using patient-derived xenograft models.

Effective systemic treatment of cancer relies on the delivery of agents with optimal therapeutic potential. The molecular age of medicine has provided genomic tools that can identify a large number of potential therapeutic targets in individual patients, heralding the promise of personalized treatment. However, determining which potential targets actually drive tumor growth and should be prioritized for therapy is challenging. Indeed, reliable molecular matches of target and therapeutic agent have been stringently validated in the clinic for only a small number of targets. Patient-derived xenografts (PDXs) are tumor models developed in immunocompromised mice using tumor procured directly from the patient. As patient surrogates, PDX models represent a powerful tool for addressing individualized therapy. Challenges include humanizing the immune system of PDX models and ensuring high quality molecular annotation, in order to maximize insights for the clinic. Importantly, PDX can be sampled repeatedly and in parallel, to reveal clonal evolution, which may predict mechanisms of drug resistance and inform therapeutic strategy design.

Parameterization of Org27569: an allosteric modulator of the cannabinoid CB1 G protein-coupled receptor.

The cannabinoid CB1 receptor is a class A G protein-coupled receptor (GPCR) that is the most widely expressed GPCR in the brain. Many GPCRs contain allosteric binding sites for endogenous and/or synthetic ligands, which are topographically distinct from the agonist-binding site that is known as the orthosteric site. While both endogenous and synthetic ligands that act at the CB1 orthosteric site have been known for some time, compounds that act at a CB1 allosteric site have only recently been discovered. The most studied of these is 5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-ylphenyl)ethyl]amide (Org27569). Because allosteric ligands are thought to act through conformational changes in the receptor that are transmitted from the allosteric to the orthosteric site, computational studies of the structural and dynamic interactions of Org27569 with the CB1 receptor are crucial to achieve a molecular level understanding of the basis of action of this important new class of compounds. To date, such computational studies have not been possible due to the lack of a complete set of molecular mechanics force field parameters for Org27569. Here, we present the development of missing CHARMM force field parameters for Org27569 using previously published methods and the validation and application of these new parameters using normal mode analysis and molecular dynamics simulations combined with experimental infrared measurements.

Outcome of consecutive pregnancies in a patient with Bombay (Oh) blood group.

A young lady with a rare Bombay (Oh) blood group had two successive uneventful pregnancies. Her serum contained a potent high-titre anti-H and serological as well as chemiluminescence tests, suggesting that the antibody was haemolytic. Her husband was of the normal H status. Theoretically, both babies should have been positive for the H antigen and should have suffered from haemolytic disease of the newborn. This apparent conundrum could be owing to the weak expression of the H antigens on the infant red cells.

Induction of polyomavirus-specific CD8(+) T lymphocytes by distinct dendritic cell subpopulations.

Dendritic cells are pivotal antigen-presenting cells for generating adaptive T-cell responses. Here, we show that dendritic cells belonging to either the myeloid-related or lymphoid-related subset are permissive for infection by mouse polyomavirus and, when loaded with a peptide corresponding to the immunodominant anti-polyomavirus CD8(+) T-cell epitope or infected by polyomavirus, are each capable of driving expansion of primary polyomavirus-specific CD8(+) T-cell responses in vivo.

Effect of antipronation tape and temporary orthotic on vertical navicular height before and after exercise.

STUDY DESIGN: A randomized controlled, crossover, within-subjects study evaluating 2 antipronation treatments. OBJECTIVES: To investigate the antipronation effect of 2 treatments designed to reduce abnormal pronation, and the effect of an exercise challenge on the treatments. BACKGROUND: Control of abnormal pronation in order to ameliorate inappropriate stresses on injured soft tissues is frequently sought in the treatment of overuse injuries of the lower limb. Tape and temporary soft orthotics are used to control abnormal pronation. The effects of these treatments remain largely untested. METHODS AND MEASURES: Fourteen subjects (age = 23.8 +/- 3.5 years) who had at least a 10-mm navicular drop were studied. The dependent variable was vertical navicular height. The two independent variables were the treatment conditions (temporary felt orthotics, augmented LowDye tape, and control) and the exercise challenge (0, 10, and 20 minutes of controlled jogging). The subjects' vertical navicular height was measured before and after the application of the treatment conditions, and then after 10 and 20 minutes of jogging. RESULTS: Tape and orthotic treatments produced approximately a 19% and 14% increase in vertical navicular height, respectively, which were both significantly greater than the control condition (0%). The treatment effect, although significantly diminished following exercise challenge, remained superior to control (6.5% for orthotic and 3.5% for tape compared to -7.3% for control). CONCLUSION: Antipronation tape and temporary orthotics help to control excessive foot pronation initially after application and following exercise. These treatments may be useful in the assessment and treatment of lower limb injuries that are associated with abnormal foot pronation.

Polyomavirus-infected dendritic cells induce antiviral CD8(+) T lymphocytes.

CD8(+) T cells are critical for the clearance of acute polyomavirus infection and the prevention of polyomavirus-induced tumors, but the antigen-presenting cell(s) involved in generating polyomavirus-specific CD8(+) T cells have not been defined. We investigated whether dendritic cells and macrophages are permissive for polyomavirus infection and examined their potential for inducing antiviral CD8(+) T cells. Although dendritic cells and macrophages both supported productive polyomavirus infection, dendritic cells were markedly more efficient at presenting the immunodominant viral epitope to CD8(+) T cells. Additionally, infected dendritic cells, but not infected macrophages, primed anti-polyomavirus CD8(+) T cells in vivo. Treatment with Flt3 ligand, a hematopoietic growth factor that dramatically expands the number of dendritic cells, markedly enhanced the magnitude of virus-specific CD8(+) T-cell responses during acute infection and the pool of memory anti-polyomavirus CD8(+) T cells. These findings suggest that virus-infected dendritic cells induce polyomavirus-specific CD8(+) T cells in vivo and raise the potential for their use as cellular adjuvants to promote CD8(+) T cell surveillance against polyomavirus-induced tumors.

A chemiluminescence test for predicting the outcome of transfusing incompatible blood.

A chemiluminescent test (CLT) which measures the metabolic response of human monocytes to sensitized red cells was developed to distinguish antibodies capable of causing the increased destruction of transfused incompatible red cells from antibodies which are clinically benign. Thirty sera containing IgG antibodies to high-frequency antigens were tested; 27 of these sera were also tested using the monocyte monolayer assay (MMA). The clinical significance of antibodies in 14 of the sera was known: three (anti-Ata (two), -JMH) caused accelerated clearance of 51Cr-labelled cells, five (anti-'MiIII', -Yta, three unidentified) caused haemolytic transfusion reactions and six (anti-Yta, -Ge, -JMH, -Xga, -Kna (two)) did not appear to affect red cell survival. Overall, results from the MMA and CLT showed good agreement; seven sera were negative in both assays, 18 sera were positive in both assays and two sera were positive in the MMA but negative in the CLT. There was no clear relationship between the activity of different antibodies and the level of sensitization as determined by flow cytometry. Antibody activity could be either increased or decreased by incubation of sensitized red cells with fresh serum. MMA results were in concordance with the clinical significance of antibodies where known in eight of 10 cases. CLT results were in concordance with clinical significance in 12 of 14 cases. Both assays gave false-positive results with serum from a patient with anti-Kna who had received red cell transfusions without adverse effect. This appeared to be due to the ability of anti-Kna to cross-link complement receptor 1 (CR1) on red cells to CR1 on monocytes; negative results were obtained using autologous monocytes.