Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the α3 domain of MHC I molecules

THE α1 and α2 domains of major histocompatibility complex (MHC) class I molecules function in the binding and presentation of foreign peptides to the T-cell antigen receptor and control both negative and positive selection of the T-cell repertoire. Although the α3 domain of class I is not involved in peptide binding, it does interact with the T-cell accessory molecule, CDS. CDS is important in the selection of T cells as anti-CDS antibody injected into perinatal mice interfers with this process. We previously used a hybrid class I molecule with the α1/α2 domains from L^d and the α3 domain from Q7^b and showed that this molecule binds an L^d-restricted peptide but does not interact with CD8-dependent cytotoxic T lymphocytes. Expression of this molecule in transgenic mice fails to negatively select a subpopulation of anti-L^d cytotoxic T lymphocytes. In addition, positive selection of virus-specific L^d-restricted cytotoxic T lymphocytes does not occur. We conclude that besides the α1/α2 domains of class I, the α3 domain plays an important part in both positive and negative selection of antigen-specific cells

Breastfeeding patterns and exposure to suboptimal breastfeeding among children in developing countries: review and analysis of nationally representative surveys

BACKGROUND: Suboptimal breastfeeding is associated with higher mortality among infants and young children in the developing world. We describe patterns in 'exclusive breastfeeding' and 'any breastfeeding' rates and quantify exposure to suboptimal breastfeeding among children aged two years or younger in developing countries. METHODS: We reviewed nationally representative surveys that collected data on breastfeeding rates in 94 developing countries. Surveys were categorized by completeness and comprehensiveness of data. Complete and comprehensive data were analysed with minimum chi-square regression. With a fitting procedure, estimated parameters were used to impute missing observations for incomplete or non-comprehensive surveys. Breastfeeding indicators were calculated and are reported for 135 developing countries by UN region. RESULTS: Amongst infants aged six months or younger in the developing world, the prevalence of exclusive breastfeeding is 39% and the prevalence of no breastfeeding is 5.6%. The prevalence of continued breastfeeding is 86% and 68% for infants and children aged 6–11 and 12–23 months, respectively, in the developing world. Imputation expands population coverage of indicators, especially for infants. Breastfeeding trends are highly linear and estimated parameters defining the age-specific attrition hazard are robust. Survey-reported rates, particularly for exclusive breastfeeding, appear to have systematic upward bias, and exposure estimates must be considered conservative. CONCLUSIONS: Compliance with breastfeeding recommendations in developing countries is low, and more attention should be given to increasing breastfeeding – especially exclusive breastfeeding – and to monitoring trends. Although the introduction of more standardized and better validated survey instruments is desirable, since data coverage, completeness and comprehensiveness are extensive, global exposure assessment is relatively robust. Moreover, the regularity of breastfeeding patterns show existing survey data capture real biological and social phenomena. Our method for the analysis of breastfeeding rates provides a potent tool for summarizing trends, validating observations, translating and extrapolating indicators (as well as projecting and imputing estimates when necessary) and should support more effective child health monitoring

Ecological implications of a flower size/number trade-off in tropical forest trees

Peer reviewedPublisher PD

Alarm Pheromones and Chemical Communication in Nymphs of the Tropical Bed Bug Cimex hemipterus (Hemiptera: Cimicidae)

The recent resurge of bed bug infestations (Cimex spp.; Cimicidae) and their resistance to commonly used pesticides calls for alternative methods of control. Pheromones play an important role in environmentally sustainable methods for the management of many pest insects and may therefore be applicable for the control of bed bugs. The tropical bed bug, Cimex hemipterus, is a temporary ectoparasite on humans and causes severe discomfort. Compared to the common bed bug, Cimex lectularius, little is known about the chemical signalling and pheromone-based behaviour of the tropical species. Here, we show that the antennal morphology and volatile emission of C. hemipterus closely resembles those of C. lectularius and we test their behavioural responses to conspecific odour emissions. Two major volatiles are emitted by male, female and nymph C. hemipterus under stress, (E)-2-hexenal and (E)-2-octenal. Notably, nymph emissions show contrasting ratios of these compounds to adults and are further characterized by the addition of 4-oxo-(E)-2-hexenal and 4-oxo-(E)-2-octenal. The discovery of this nymph pheromone in C. hemipterus is potentially the cause of a repellent effect observed in the bio-tests, where nymph odours induce a significantly stronger repellent reaction in conspecifics than adult odours. Our results suggest that pheromone-based pest control methods developed for C. lectularius could be applicable to C. hemipterus, with the unique nymph blend showing promising practical properties

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Migraine and sleep apnea in the general population

Objective is to investigate the relationship between migraine and obstructive sleep apnea in the general population. A cross-sectional population-based study. A random age and gender stratified sample of 40,000 persons aged 20–80 years residing in Akershus, Hedmark or Oppland County, Norway, were drawn by the National Population Register. A postal questionnaire containing the Berlin Questionnaire was used to classify respondents to be of either high or low risk of obstructive sleep apnea. 376 persons with high risk and 157 persons with low risk of sleep apnea aged 30–65 years were included for further investigations. They underwent an extensive clinical interview, a physical and a neurological examination by physicians, and in-hospital polysomnography. Those with apnea hypopnoea index (AHI) ≥5 were classified with obstructive sleep apnea. Migraine without aura (MO) and migraine with aura (MA) was diagnosed according to the International Classification of Headache Disorders. MO and MA occurred in 12.5 and 6.8% of the participants with obstructive sleep apnea. The logistic regression analyses showed no relationship between the two types of migraine and obstructive sleep apnea, with adjusted odds ratios for MO 1.15 (0.65–2.06) and MA 1.15 (0.95–2.39). Further, estimates using cutoff of moderate (AHI ≥ 15) and severe (AHI ≥ 30) obstructive sleep apnea, did not reveal any significant relationship between migraine and the AHI. Migraine and obstructive sleep apnea are unrelated in the general population

Order without design

Experimental reality in molecular and cell biology, as revealed by advanced research technologies and methods, is manifestly inconsistent with the design perspective on the cell, thus creating an apparent paradox: where do order and reproducibility in living systems come from if not from design

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Expression of Drosophila Adenosine Deaminase in Immune Cells during Inflammatory Response

Extra-cellular adenosine is an important regulator of inflammatory responses. It is generated from released ATP by a cascade of ectoenzymes and degraded by adenosine deaminase (ADA). There are two types of enzymes with ADA activity: ADA1 and ADGF/ADA2. ADA2 activity originates from macrophages and dendritic cells and is associated with inflammatory responses in humans and rats. Drosophila possesses a family of six ADGF proteins with ADGF-A being the main regulator of extra-cellular adenosine during larval stages. Herein we present the generation of a GFP reporter for ADGF-A expression by a precise replacement of the ADGF-A coding sequence with GFP using homologous recombination. We show that the reporter is specifically expressed in aggregating hemocytes (Drosophila immune cells) forming melanotic capsules; a characteristic of inflammatory response. Our vital reporter thus confirms ADA expression in sites of inflammation in vivo and demonstrates that the requirement for ADA activity during inflammatory response is evolutionary conserved from insects to vertebrates. Our results also suggest that ADA activity is achieved specifically within sites of inflammation by an uncharacterized post-transcriptional regulation based mechanism. Utilizing various mutants that induce melanotic capsule formation and also a real immune challenge provided by parasitic wasps, we show that the acute expression of the ADGF-A protein is not driven by one specific signaling cascade but is rather associated with the behavior of immune cells during the general inflammatory response. Connecting the exclusive expression of ADGF-A within sites of inflammation, as presented here, with the release of energy stores when the ADGF-A activity is absent, suggests that extra-cellular adenosine may function as a signal for energy allocation during immune response and that ADGF-A/ADA2 expression in such sites of inflammation may regulate this role