Associations of air pollution exposures in preconception and pregnancy with birth outcomes and infant neurocognitive development: analysis of the Complex Lipids in Mothers and Babies (CLIMB) prospective cohort in Chongqing, China.

OBJECTIVES: To investigate the associations of traffic-related air pollution exposures in early pregnancy with birth outcomes and infant neurocognitive development. DESIGN: Cohort study. SETTING: Eligible women attended six visits in the maternity clinics of two centres, the First Affiliated Hospital of Chongqing Medical University and Chongqing Health Centre for Women and Children. PARTICIPANTS: Women who were between 20 and 40 years of age and were at 11-14 weeks gestation with a singleton pregnancy were eligible for participation. Women were excluded if they had a history of premature delivery before 32 weeks of gestation, maternal milk allergy or aversion or severe lactose intolerance. 1273 pregnant women enrolled in 2015-2016 and 1174 live births were included in this analysis. EXPOSURES: Air pollution concentrations at their home addresses, including particulate matter with diameter ≤2.5 µm (PM2.5) and nitrogen dioxide (NO2), during pre-conception and each trimester period were estimated using land-use regression models. OUTCOME MEASURES: Birth outcomes (ie, birth weight, birth length, preterm birth, low birth weight, large for gestational age and small for gestational age (SGA) status) and neurodevelopment outcomes measured by the Chinese version of Bayley Scales of Infant Development. RESULTS: An association between SGA and per-IQR increases in NO2 was found in the first trimester (OR: 1.57, 95% CI: 1.06 to 2.32) and during the whole pregnancy (OR: 1.33, 99% CI: 1.01 to 1.75). Both PM2.5 and NO2 exposure in the 90 days prior to conception were associated with lower Psychomotor Development Index scores (ß: -6.15, 95% CI: -8.84 to -3.46; ß: -2.83, 95% CI: -4.27 to -1.39, respectively). Increased NO2 exposure was associated with an increased risk of psychomotor development delay during different trimesters of pregnancy. CONCLUSIONS: Increased exposures to NO2 during pregnancy were associated with increased risks of SGA and psychomotor development delay, while increased exposures to both PM2.5 and NO2 pre-conception were associated with adverse psychomotor development outcomes at 12 months of age. TRIAL REGISTRATION NUMBER: ChiCTR-IOR-16007700.

Conservation implications of a mismatch between data availability and demographic impact.

Cost-effective use of limited conservation resources requires understanding which data most contribute to alleviating biodiversity declines. Interventions might reasonably prioritise life-cycle transitions with the greatest influence on population dynamics, yet some contributing vital rates are particularly challenging to document. This risks managers making decisions without sufficient empirical coverage of the spatiotemporal variation experienced by the species. Here, we aimed to explore whether the number of studies contributing estimates for a given life-stage transition aligns with that transition's demographic impact on population growth rate, λ. We parameterised a matrix population model using meta-analysis of vital rates for the common eider (Somateria mollissima), an increasingly threatened yet comparatively data-rich species of seaduck, for which some life stages are particularly problematic to study. Female common eiders exhibit intermittent breeding, with some established breeders skipping one or more years between breeding attempts. Our meta-analysis yielded a breeding propensity of 0.72, which we incorporated into our model with a discrete and reversible 'nonbreeder' stage (to which surviving adults transition with a probability of 0.28). The transitions between breeding and nonbreeding states had twice the influence on λ than fertility (summed matrix-element elasticities of 24% and 11%, respectively), whereas almost 15 times as many studies document components of fertility than breeding propensity (n = 103 and n = 7, respectively). The implications of such mismatches are complex because the motivations for feasible on-the-ground conservation actions may be different from what is needed to reduce uncertainty in population projections. Our workflow could form an early part of the toolkit informing future investment of finite resources, to avoid repeated disconnects between data needs and availability thwarting evidence-led conservation.

Temporal correlations among demographic parameters are ubiquitous but highly variable across species.

Temporal correlations among demographic parameters can strongly influence population dynamics. Our empirical knowledge, however, is very limited regarding the direction and the magnitude of these correlations and how they vary among demographic parameters and species' life histories. Here, we use long-term demographic data from 15 bird and mammal species with contrasting pace of life to quantify correlation patterns among five key demographic parameters: juvenile and adult survival, reproductive probability, reproductive success and productivity. Correlations among demographic parameters were ubiquitous, more frequently positive than negative, but strongly differed across species. Correlations did not markedly change along the slow-fast continuum of life histories, suggesting that they were more strongly driven by ecological than evolutionary factors. As positive temporal demographic correlations decrease the mean of the long-run population growth rate, the common practice of ignoring temporal correlations in population models could lead to the underestimation of extinction risks in most species.

Inferring transient dynamics of human populations from matrix non-normality.

In our increasingly unstable and unpredictable world, population dynamics rarely settle uniformly to long-term behaviour. However, projecting period-by-period through the preceding fluctuations is more data-intensive and analytically involved than evaluating at equilibrium. To efficiently model populations and best inform policy, we require pragmatic suggestions as to when it is necessary to incorporate short-term transient dynamics and their effect on eventual projected population size. To estimate this need for matrix population modelling, we adopt a linear algebraic quantity known as non-normality. Matrix non-normality is distinct from normality in the Gaussian sense, and indicates the amplificatory potential of the population projection matrix given a particular population vector. In this paper, we compare and contrast three well-regarded metrics of non-normality, which were calculated for over 1000 age-structured human population projection matrices from 42 European countries in the period 1960 to 2014. Non-normality increased over time, mirroring the indices of transient dynamics that peaked around the millennium. By standardising the matrices to focus on transient dynamics and not changes in the asymptotic growth rate, we show that the damping ratio is an uninformative predictor of whether a population is prone to transient booms or busts in its size. These analyses suggest that population ecology approaches to inferring transient dynamics have too often relied on suboptimal analytical tools focussed on an initial population vector rather than the capacity of the life cycle to amplify or dampen transient fluctuations. Finally, we introduce the engineering technique of pseudospectra analysis to population ecology, which, like matrix non-normality, provides a more complete description of the transient fluctuations than the damping ratio. Pseudospectra analysis could further support non-normality assessment to enable a greater understanding of when we might expect transient phases to impact eventual population dynamics.

Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders.

DETQ, an allosteric potentiator of the dopamine D1 receptor, was tested in therapeutic models that were known to respond to D1 agonists. Because of a species difference in affinity for DETQ, all rodent experiments used transgenic mice expressing the human D1 receptor (hD1 mice). When given alone, DETQ reversed the locomotor depression caused by a low dose of reserpine. DETQ also acted synergistically with L-DOPA to reverse the strong hypokinesia seen with a higher dose of reserpine. These results indicate potential as both monotherapy and adjunct treatment in Parkinson's disease. DETQ markedly increased release of both acetylcholine and histamine in the prefrontal cortex, and increased levels of histamine metabolites in the striatum. In the hippocampus, the combination of DETQ and the cholinesterase inhibitor rivastigmine increased ACh to a greater degree than either agent alone. DETQ also increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB in the striatum, consistent with enhanced synaptic plasticity. In the Y-maze, DETQ increased arm entries but (unlike a D1 agonist) did not reduce spontaneous alternation between arms at high doses. DETQ enhanced wakefulness in EEG studies in hD1 mice and decreased immobility in the forced-swim test, a model for antidepressant-like activity. In rhesus monkeys, DETQ increased spontaneous eye-blink rate, a measure that is known to be depressed in Parkinson's disease. Together, these results provide support for potential utility of D1 potentiators in the treatment of several neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, cognitive impairment in schizophrenia, and major depressive disorder.

Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice.

Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (ß-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1-/- mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1-/- mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes.

Mouse models of neurological disorders--a comparison of heritable and acquired traits.

Human neurological disorders include a wide range of illnesses which have a disproportionately high prevalence in the increasingly populous geriatric community. Any research effort directed at discovering the aetiology of neurological disease is greatly enhanced with in vivo models of the disease of interest. Scientific research incorporating the use of mice has advanced rapidly in the last three decades. Relatively simple to breed, maintain and train, mice have many advantages over other species for use in research. More than a century of selective breeding has provided investigators with a rich gene pool and sub-strain diversity from which to choose for their research. Thus the dramatic increase in genetic screening and gene engineering that has occurred in research in recent decades has enabled the generation of a multitude of mouse models. This review discusses the relative utility of mouse models in which a heritable or non-heritable (acquired) manipulation has been used to model a specified trait of a human neurological disorder. The techniques used in deriving useful genetic alterations or modifications and in generating acquired mouse models are outlined with examples of each provided.

Autoradiographical imaging of PPARgamma agonist effects on PBR/TSPO binding in TASTPM mice.

Chronic inflammation is known to occur in the brains of Alzheimer's Disease (AD) patients, including the presence of activated microglia close to amyloid plaques. We utilised real time autoradiography and immunohistochemistry to investigate microglial activation and the potential anti-inflammatory effects of PPARgamma agonists in the Thy-1 APP695swe/Thy-1 PS-1.M146V (TASTPM) overexpressing transgenic mouse model of AD. An age dependent increase in specific [3H](R)-PK11195 binding to peripheral benzodiazepine receptors (PBR)/translocator protein (18 kDa) (TSPO) was observed in the cortex of TASTPM mice compared to wild type mice, indicative of microglial activation. This was consistent with immunohistochemical data showing age-dependent increases in CD68 immunoreactivity co-localised with amyloid beta (Abeta) deposits. In 10 month old TASTPM mice, pioglitazone (20 mg/kg) and ciglitazone (50 mg/kg) significantly reduced [3H](R)-PK11195 and [3H]DPA-713 binding in cortex and hippocampus, indicative of reduced microglial activation. In AD brain, significant [3H](R)-PK11195 and [3H]DPA-713 binding was observed across all stages of the disease. These results support the use of PBR/TSPO autoradiography in TASTPM mice as a functional readout of microglial activation to assess anti-inflammatory drugs prior to evaluation in AD patients.

Adaptation mechanisms, eccentricity profiles, and clinical implementation of red-on-white perimetry.

PURPOSE: To determine the visual adaptation and retinal eccentricity profiles for red flickering and static test stimuli and report a clinical implementation of these stimuli in visual perimetry. METHODS: The adaptation profile for red-on-white perimetry stimuli was measured using a threshold vs. intensity (TvI) paradigm at 0 degree and 12 degrees eccentricity and by comparing the eccentricity-related sensitivity change for red and white, static, and flickering targets in young normal trichromats (n = 5) and a group of dichromats (n = 5). A group of older normal control observers (n = 30) were tested and retinal disease was evaluated in persons having age-related maculopathy (n = 35) and diabetes (n = 12). RESULTS: Adaptation and eccentricity profiles indicate red static and flickering targets are detected by two mechanisms in the paramacular region, and a single mechanism for >5 degrees eccentricity. The group data for the older normal observers has a high level of inter-observer variability with a generalized reduction in sensitivity across the entire visual field. Group data for the participants with age-related maculopathy show reduced sensitivities that were pronounced in the central retina. The group data for the diabetic observers showed sensitivities that were reduced at all eccentricities. The disease-related sensitivity decline was more apparent with red than white stimuli. CONCLUSIONS: The adaptation profile and change in sensitivity with retinal eccentricity for the red-on-white perimetric stimuli are consistent with two detection processes. In the macula, the putative detection mechanism is color-opponent with static targets and non-opponent with flickering targets. At peripheral field locations, the putative detection mechanism is non-opponent for both static and flicker targets. The long-wavelength stimuli are less affected by the preretinal absorption common to aging. Red-on-white static and flicker perimetry may be useful for monitoring retinal disease, revealing greater abnormalities compared with conventional white-on-white perimetry, especially in the macula where two detection mechanisms are found.

Elevated levels of amyloid precursor protein in muscle of patients with amyotrophic lateral sclerosis and a mouse model of the disease.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease defined by motor neuron loss. Transgenic mouse models show features that closely mimic those seen in the clinical situation, reflected in the molecular changes observed in mouse models and in tissues from patients. We report a dramatic increase in the expression of amyloid precursor protein (APP) in the hindlimb muscles, but not the spinal cord of the G93A transgenic mouse model, significantly before the appearance of clinical abnormalities. APP levels were unchanged in nontransgenic mice and in mice overexpressing human wild-type Cu/Zn-dependent superoxide dismutase 1 (SOD1). Preliminary results indicate a similar change in APP expression in human deltoid muscle samples from ALS patients compared with age-matched controls. The inhibitory role of APP in innervation at the neuromuscular junction and increased expression in inclusion-body myositis suggest that presymptomatic upregulation of APP may be consistent with a potential role for APP in ALS pathology.

Imaging and spatial distribution of beta-amyloid peptide and metal ions in Alzheimer's plaques by laser ablation-inductively coupled plasma-mass spectrometry.

Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) has been developed as a new strategy for detection and imaging of beta-amyloid protein in immunohistochemical sections from the brains of a transgenic mouse model of Alzheimer's disease. The distribution of beta-amyloid deposits in tissue was based on measurement of Eu- and Ni-coupled antibodies. The laser-based methodologies (spot ablation, single line raster, and two-dimensional imaging) were also used to detect and map trace element distributions and thus provide a novel probe for both elemental and protein data. We also report the combination of laser capture microdissection with LA-ICP-MS as an alternative strategy for microanalysis of immunohistochemical sections.

Production of transgenic and mutant mouse models.

Manipulation of the rodent genome by deliberately inserting (transgenic) or removing (knockout) a gene of interest or indeed by selectively breeding animals with a spontaneous or random mutation producing a trait of interest has been developed over several years. Mouse "fanciers" have been selectively breeding interesting mice since the turn of the last century to produce a plethora of different background strains of the common house mouse (Mus musculus). Rat (Rattus norvegicus) strain development has also proceeded with selective breeding, although the range of strains is more limited. The deliberate and targeted manipulation of the mouse genome has been with us for over two decades, with the rat genome a more recent addition, and yet this technology has been limited to a very narrow range of genes. With the complete mapping of the mouse genome (and the rat genome soon to follow), the powerful techniques of transgenic and knockout rodent production can be applied to the numerous genes whose expression is altered in existing stroke models.

BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes.

BACE1 is a key enzyme in the generation of Abeta, the major component of senile plaques in the brains of Alzheimer's disease patients. We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-length coding sequence of human BACE1 preceding an internal ribosome entry site element followed by a LacZ reporter gene. These animals exhibit a bold, exploratory behavior and show elevated 5-hydroxytryptamine turnover. We have also generated a knockout mouse in which LacZ replaces the first exon of murine BACE1. Interestingly these animals show a contrasting behavior, being timid and less exploratory. Despite these clear differences both mouse lines are viable and fertile with no changes in morbidity. These results suggest an unexpected role for BACE1 in neurotransmission, perhaps through changes in amyloid precursor protein processing and Abeta levels.

Lipid rafts mediate the interaction between myelin-associated glycoprotein (MAG) on myelin and MAG-receptors on neurons.

The interaction between myelin-associated glycoprotein (MAG), expressed at the periaxonal membrane of myelin, and receptors on neurons initiates a bidirectional signalling system that results in inhibition of neurite outgrowth and maintenance of myelin integrity. We show that this involves a lipid-raft to lipid-raft interaction on opposing cell membranes. MAG is exclusively located in low buoyancy Lubrol WX-insoluble membrane fractions isolated from whole brain, primary oligodendrocytes, or MAG-expressing CHO cells. Localisation within these domains is dependent on cellular cholesterol and occurs following terminal glycosylation in the trans-Golgi network, characteristics of association with lipid rafts. Furthermore, a recombinant form of MAG interacts specifically with lipid-raft fractions from whole brain and cultured cerebellar granule cells, containing functional MAG receptors GT1b and Nogo-66 receptor and molecules required for transduction of signal from MAG into neurons. The localisation of both MAG and MAG receptors within lipid rafts on the surface of opposing cells may create discrete areas of high avidity multivalent interaction, known to be critical for signalling into both cell types. Localisation within lipid rafts may provide a molecular environment that facilitates the interaction between MAG and multiple receptors and also between MAG ligands and molecules involved in signal transduction.