Publishing trends of journals with manuscripts in PubMed Central: changes from 2008-2009 to 2015-2016.

OBJECTIVE: The National Institutes of Health (NIH) public access policy mandates that all articles containing NIH-funded research must be deposited into PubMed Central (PMC). The aim of this study was to assess publishing trends of journals that were not selected for the National Library of Medicine (NLM) collection but contain NIH-funded articles submitted to PMC in compliance with the public access policy. In addition, the authors investigated the degree to which NIH-funded research is published in journals that NLM does not collect due to concerns with the publishers. METHODS: We analyzed bibliographic data from the NIH Manuscript Submission system for journals that were not selected for the NLM collection from August 2015 to August 2016. Publications (n=738) were analyzed by language, publishing country, publishing format, and subject, and the results were compared to a similar study of 2008-2009 data. In addition, publications were analyzed by whether their publishers are collected by NLM, as determined by transparency and adherence to publishing best practices. RESULTS: Only a few differences were found between the studies. Most notably, while both studies revealed that most journals were not selected for the NLM collection because they were out of scope (i.e., not biomedical), we noted an increase in 2015-2016 in biomedical journals containing NIH-funded articles that were not added to the collection due to concerns with the publishers. CONCLUSIONS: While the current number of NIH-funded manuscripts being published by publishers that are not collected by NLM remains quite small, we noted a substantial increase between 2008-2009 and 2015-2016.

Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood-brain barrier impairment.

Pulmonary exposure to multiwalled carbon nanotubes (MWCNTs) causes indirect systemic inflammation through unknown pathways. MWCNTs translocate only minimally from the lungs into the systemic circulation, suggesting that extrapulmonary toxicity may be caused indirectly by lung-derived factors entering the circulation. To assess a role for MWCNT-induced circulating factors in driving neuroinflammatory outcomes, mice were acutely exposed to MWCNTs (10 or 40 µg/mouse) via oropharyngeal aspiration. At 4 h after MWCNT exposure, broad disruption of the blood-brain barrier (BBB) was observed across the capillary bed with the small molecule fluorescein, concomitant with reactive astrocytosis. However, pronounced BBB permeation was noted, with frank albumin leakage around larger vessels (>10 µm), overlain by a dose-dependent astroglial scar-like formation and recruitment of phagocytic microglia. As affirmed by elevated inflammatory marker transcription, MWCNT-induced BBB disruption and neuroinflammation were abrogated by pretreatment with the rho kinase inhibitor fasudil. Serum from MWCNT-exposed mice induced expression of adhesion molecules in primary murine cerebrovascular endothelial cells and, in a wound-healing in vitro assay, impaired cell motility and cytokinesis. Serum thrombospondin-1 level was significantly increased after MWCNT exposure, and mice lacking the endogenous receptor CD36 were protected from the neuroinflammatory and BBB permeability effects of MWCNTs. In conclusion, acute pulmonary exposure to MWCNTs causes neuroinflammatory responses that are dependent on the disruption of BBB integrity.

Exposure of neonatal rats to alcohol has differential effects on neuroinflammation and neuronal survival in the cerebellum and hippocampus.

BACKGROUND: Fetal alcohol exposure is a leading cause of preventable birth defects, yet drinking during pregnancy remains prevalent worldwide. Studies suggest that activation of the neuroimmune system plays a role in the effects of alcohol exposure during the rodent equivalent to the third trimester of human pregnancy (i.e., first week of neonatal life), particularly by contributing to neuronal loss. Here, we performed a comprehensive study investigating differences in the neuroimmune response in the cerebellum and hippocampus, which are important targets of third trimester-equivalent alcohol exposure. METHODS: To model heavy, binge-like alcohol exposure during this period, we exposed rats to alcohol vapor inhalation during postnatal days (P)3-5 (blood alcohol concentration = 0.5 g/dL). The cerebellar vermis and hippocampus of rat pups were analyzed for signs of glial cell activation and neuronal loss by immunohistochemistry at different developmental stages. Cytokine production was measured by reverse transcriptase polymerase chain reaction during peak blood alcohol concentration and withdrawal periods. Additionally, adolescent offspring were assessed for alterations in gait and spatial memory. RESULTS: We found that this paradigm causes Purkinje cell degeneration in the cerebellar vermis at P6 and P45; however, no signs of neuronal loss were found in the hippocampus. Significant increases in pro-inflammatory cytokines were observed in both brain regions during alcohol withdrawal periods. Although astrocyte activation occurred in both the hippocampus and cerebellar vermis, microglial activation was observed primarily in the latter. CONCLUSIONS: These findings suggest that heavy, binge-like third trimester-equivalent alcohol exposure has time- and brain region-dependent effects on cytokine levels, morphological activation of microglia and astrocytes, and neuronal survival.

Effect of repeated alcohol exposure during the third trimester-equivalent on messenger RNA levels for interleukin-1ß, chemokine (C-C motif) ligand 2, and interleukin 10 in the developing rat brain after injection of lipopolysaccharide.

Microglia undergo maturation during the third trimester of human development (equivalent to the first 1-2 weeks of postnatal life in rodents), during which these cells may be particularly sensitive to insult. Alcohol exposure during this period can activate the neuroimmune system, an effect that may contribute to the pathophysiology of fetal alcohol spectrum disorders. Here, we investigated whether repeated alcohol exposure during the third trimester-equivalent in rats has a priming effect on the neuroimmune response to injection of bacterial lipopolysaccharide (LPS). Pups were exposed to alcohol in vapor chambers for 4 h daily from postnatal day (PD)2 to PD16 (peak blood alcohol concentrations ∼150 mg/dL). On PD17, rats were injected with either saline or LPS (50 µg/kg) and the frontal cortex, cerebellar vermis, and dentate gyrus were collected 2 h later. Messenger RNA (mRNA) levels for the pro-inflammatory agents interleukin 1ß (IL-1ß) and chemokine (C-C) motif ligand 2 (CCL2), as well as levels of the anti-inflammatory cytokine interleukin 10 (IL-10), were measured using reverse transcriptase polymerase chain reaction. LPS consistently increased IL-1ß and CCL2 mRNA levels in the dentate gyrus, frontal cortex, and cerebellum of both male and female rats. Furthermore, the LPS-induced increase of IL-1ß mRNA levels was significantly blunted in the frontal cortex of alcohol-exposed female rats. Conversely, LPS only minimally affected IL-10 mRNA expression and there were no significant differences between air- and alcohol-exposed rats. Taken together with the literature regarding the effect of third-trimester alcohol exposure on the neuroimmune system, our findings suggest that chronic exposure to lower levels is less disruptive to the neuroimmune system than binge-like exposure to high doses of alcohol.

Construction of vapor chambers used to expose mice to alcohol during the equivalent of all three trimesters of human development.

Exposure to alcohol during development can result in a constellation of morphological and behavioral abnormalities that are collectively known as Fetal Alcohol Spectrum Disorders (FASDs). At the most severe end of the spectrum is Fetal Alcohol Syndrome (FAS), characterized by growth retardation, craniofacial dysmorphology, and neurobehavioral deficits. Studies with animal models, including rodents, have elucidated many molecular and cellular mechanisms involved in the pathophysiology of FASDs. Ethanol administration to pregnant rodents has been used to model human exposure during the first and second trimesters of pregnancy. Third trimester ethanol consumption in humans has been modeled using neonatal rodents. However, few rodent studies have characterized the effect of ethanol exposure during the equivalent to all three trimesters of human pregnancy, a pattern of exposure that is common in pregnant women. Here, we show how to build vapor chambers from readily obtainable materials that can each accommodate up to six standard mouse cages. We describe a vapor chamber paradigm that can be used to model exposure to ethanol, with minimal handling, during all three trimesters. Our studies demonstrate that pregnant dams developed significant metabolic tolerance to ethanol. However, neonatal mice did not develop metabolic tolerance and the number of fetuses, fetus weight, placenta weight, number of pups/litter, number of dead pups/litter, and pup weight were not significantly affected by ethanol exposure. An important advantage of this paradigm is its applicability to studies with genetically-modified mice. Additionally, this paradigm minimizes handling of animals, a major confound in fetal alcohol research.

Two-year impact of personality-targeted, teacher-delivered interventions on youth internalizing and externalizing problems: a cluster-randomized trial.

OBJECTIVE: To assess the 2-year impact of teacher-delivered, brief, personality-targeted interventions on internalizing and externalizing symptoms in an adolescent U.K. sample. METHOD: This cluster-randomized trial was run in 19 London schools (N = 1,024 adolescents). Trained school-based professionals delivered two 90-minute, CBT-based group interventions targeting 1 of 4 personality-risk profiles: anxiety sensitivity, hopelessness, impulsivity, or sensation seeking. Self-report depression, anxiety, and conduct disorder symptoms were assessed at 6-month intervals. RESULTS: Interventions were associated with significantly reduced depressive, anxiety, and conduct symptoms (p < .05) over 2 years in the full sample, reduced odds of severe depressive symptoms (odds ratio [OR] = 0.74, CI = 0.58-0.96), and conduct problems (OR = 0.79, CI = 0.65-0.96), and a nonsignificant reduction in severe anxiety symptoms (OR = 0.79, CI = 0.59-1.05). Evaluating a priori personality-specific hypotheses revealed strong evidence for impulsivity-specific effects on severe conduct problems, modest evidence of anxiety sensitivity-specific effects on severe anxiety, and no evidence for hopelessness-specific effects on severe depressive symptoms. CONCLUSIONS: Brief, personality-targeted interventions delivered by educational professionals can have a clinically significant impact on mental health outcomes in high-risk youth over 2 years, as well as personality-specific intervention effects in youth most at risk for a particular problem, particularly for youth with high levels of impulsivity. Clinical trial registration information-Adventure: The Efficacy of Personality-Targeted Interventions for Substance Misuse and Other Risky Behaviors as Delivered by Educational Professionals.

Isoprene synthase genes form a monophyletic clade of acyclic terpene synthases in the TPS-B terpene synthase family.

Many plants emit significant amounts of isoprene, which is hypothesized to help leaves tolerate short episodes of high temperature. Isoprene emission is found in all major groups of land plants including mosses, ferns, gymnosperms, and angiosperms; however, within these groups isoprene emission is variable. The patchy distribution of isoprene emission implies an evolutionary pattern characterized by many origins or many losses. To better understand the evolution of isoprene emission, we examine the phylogenetic relationships among isoprene synthase and monoterpene synthase genes in the angiosperms. In this study we identify nine new isoprene synthases within the rosid angiosperms. We also document the capacity of a myrcene synthase in Humulus lupulus to produce isoprene. Isoprene synthases and (E)-ß-ocimene synthases form a monophyletic group within the Tps-b clade of terpene synthases. No asterid genes fall within this clade. The chemistry of isoprene synthase and ocimene synthase is similar and likely affects the apparent relationships among Tps-b enzymes. The chronology of rosid evolution suggests a Cretaceous origin followed by many losses of isoprene synthase over the course of evolutionary history. The phylogenetic pattern of Tps-b genes indicates that isoprene emission from non-rosid angiosperms likely arose independently.

Effectiveness of a selective, personality-targeted prevention program for adolescent alcohol use and misuse: a cluster randomized controlled trial.

CONTEXT: Selective school-based alcohol prevention programs targeting youth with personality risk factors for addiction and mental health problems have been found to reduce substance use and misuse in those with elevated personality profiles. OBJECTIVES: To report 24-month outcomes of the Teacher-Delivered Personality-Targeted Interventions for Substance Misuse Trial (Adventure trial) in which school staff were trained to provide interventions to students with 1 of 4 high-risk (HR) profiles: anxiety sensitivity, hopelessness, impulsivity, and sensation seeking and to examine the indirect herd effects of this program on the broader low-risk (LR) population of students who were not selected for intervention. DESIGN: Cluster randomized controlled trial. SETTING: Secondary schools in London, United Kingdom. PARTICIPANTS: A total of 1210 HR and 1433 LR students in the ninth grade (mean [SD] age, 13.7 [0.33] years). INTERVENTION: Schools were randomized to provide brief personality-targeted interventions to HR youth or treatment as usual (statutory drug education in class). MAIN OUTCOME MEASURES: Participants were assessed for drinking, binge drinking, and problem drinking before randomization and at 6-monthly intervals for 2 years. RESULTS: Two-part latent growth models indicated long-term effects of the intervention on drinking rates (ß = -0.320, SE = 0.145, P = .03) and binge drinking rates (ß = -0.400, SE = 0.179, P = .03) and growth in binge drinking (ß = -0.716, SE = 0.274, P = .009) and problem drinking (ß = -0.452, SE = 0.193, P = .02) for HR youth. The HR youth were also found to benefit from the interventions during the 24-month follow-up on drinking quantity (ß = -0.098, SE = 0.047, P = .04), growth in drinking quantity (ß = -0.176, SE = 0.073, P = .02), and growth in binge drinking frequency (ß = -0.183, SE = 0.092, P = .047). Some herd effects in LR youth were observed, specifically on drinking rates (ß = -0.259, SE = 0.132, P = .049) and growth of binge drinking (ß = -0.244, SE = 0.073, P = .001), during the 24-month follow-up. CONCLUSIONS: Findings further support the personality-targeted approach to alcohol prevention and its effectiveness when provided by trained school staff. Particularly novel are the findings of some mild herd effects that result from this selective prevention program. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00776685.

Magnitude of stimulation dictates the cannabinoid-mediated differential T cell response to HIVgp120.

Approximately 25% of immunocompromised HIV patients smoke marijuana for its putative therapeutic benefit. The goal of these studies was to test the hypothesis that marijuana-derived cannabinoids have immunomodulatory effects on HIV antigen-specific T cell effector function. A surrogate mouse model to induce polyclonal T cell responses against HIV(gp120) was established. THC, a marijuana-derived cannabinoid, suppressed or enhanced mouse CD8(+) T cell proliferation and the gp120-specific CTL response depending on the magnitude of the IFN-γ response. To determine the molecular mechanisms by which cannabinoids differentially modulate T cell responses, P/I or anti-CD3/CD28 antibodies were used for stimulation, and another marijuana-derived cannabinoid, CBD, was also investigated. THC or CBD suppressed or enhanced IFN-γ and IL-2 production by mouse splenocytes under optimal or suboptimal stimulation, respectively. Similar differential effects of cannabinoids on cytokine production were also observed on nuclear translocation of NFAT and with human PBMCs in response to P/I stimulation. However, THC and CBD elevated intracellular calcium, regardless of the stimulation level with P/I, suggesting that the cannabinoid-induced calcium increase provides an appropriate signal for activation in suboptimally stimulated T cells but an anergic-like signal as a result of excessive calcium in optimally stimulated T cells. Overall, these data demonstrate differential modulation by cannabinoids of a HIV antigen-specific response and identify a possible mechanism responsible for this effect.

Does moderate drinking harm the fetal brain? Insights from animal models.

Although public health campaigns advise pregnant women to abstain from ethanol, drinking during pregnancy is pervasive. Here, we highlight recent studies that have clearly demonstrated long-lasting neurobehavioral deficits in the offspring of laboratory animals exposed to moderate levels of ethanol during development. Alterations in learning, memory, motor coordination, social behavior, and stress responses were identified in these animals. Increased vulnerability to substance abuse was also demonstrated. These behavioral alterations have been associated with impairments in neurotransmitter systems, neuromodulators, and/or synaptic plasticity in several brain regions. With this review we hope to contribute to a better appreciation of the potential effects of developmental exposure to moderate ethanol levels, leading to better interventions aimed at relieving fetal alcohol spectrum disorders.

Biochemical characterization and homology modeling of methylbutenol synthase and implications for understanding hemiterpene synthase evolution in plants.

2-Methyl-3-buten-2-ol (MBO) is a five-carbon alcohol produced and emitted in large quantities by many species of pine native to western North America. MBO is structurally and biosynthetically related to isoprene and can have an important impact on regional atmospheric chemistry. The gene for MBO synthase was identified from Pinus sabiniana, and the protein encoded was functionally characterized. MBO synthase is a bifunctional enzyme that produces both MBO and isoprene in a ratio of ~90:1. Divalent cations are required for activity, whereas monovalent cations are not. MBO production is enhanced by K(+), whereas isoprene production is inhibited by K(+) such that, at physiologically relevant [K(+)], little or no isoprene emission should be detected from MBO-emitting trees. The K(m) of MBO synthase for dimethylallyl diphosphate (20 mm) is comparable with that observed for angiosperm isoprene synthases and 3 orders of magnitude higher than that observed for monoterpene and sesquiterpene synthases. Phylogenetic analysis showed that MBO synthase falls into the TPS-d1 group (gymnosperm monoterpene synthases) and is most closely related to linalool synthase from Picea abies. Structural modeling showed that up to three phenylalanine residues restrict the size of the active site and may be responsible for making this a hemiterpene synthase rather than a monoterpene synthase. One of these residues is homologous to a Phe residue found in the active site of isoprene synthases. The remaining two Phe residues do not have homologs in isoprene synthases but occupy the same space as a second Phe residue that closes off the isoprene synthase active site.

Adolescent bullying victimisation and alcohol-related problem behaviour mediated by coping drinking motives over a 12 month period.

BACKGROUND: Despite the adverse externalising risks associated with bullying victimisation, no study has investigated the underlying mechanisms of adolescent victims' engagement with alcohol. This current study investigated the development of risky coping drinking motives as a mediator in the relationship between adolescent school victimisation and alcohol-related problem behaviour using a longitudinal design over 12 months. METHOD: We recruited 324 participants, aged 13 to 15 from schools across London, England. Participants were surveyed during class time at 2 time points: baseline and 12 months. At both time points participants answered questions related to bullying victimisation, alcohol-related problem behaviour, drinking motives and the quantity by frequency of alcohol consumption. RESULTS: The relationships between victimisation, drinking and drinking motives were investigated using Pearson correlations. Path analysis showed that victimisation leads both directly and indirectly, through coping motives to alcohol-related problems, rather than to the quantity and frequency of alcohol use. Significance of mediation was tested using 5000 bias corrected and accelerated bootstrapped intervals. Baseline victimisation was significantly correlated with baseline alcohol-related problem behaviour and predictive of future problems at 12 months. Drinking to cope at 12 months partially mediated the relationship between baseline victimisation and alcohol-related problems at 12 months. CONCLUSIONS: Results show that victims of bullying are drinking alcohol in a risky style, partly due to the development of self medicating drinking behaviour. Victims of bullying could therefore benefit from coping skills interventions targeting negative affect regulation in order to reduce the risk for future alcohol misuse.