A Upf3b-mutant mouse model with behavioral and neurogenesis defects.

Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, cause intellectual disability (ID) and are strongly associated with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ). Here, we report the generation and characterization of mice harboring a null Upf3b allele. These Upf3b-null mice exhibit deficits in fear-conditioned learning, but not spatial learning. Upf3b-null mice also have a profound defect in prepulse inhibition (PPI), a measure of sensorimotor gating commonly deficient in individuals with SCZ and other brain disorders. Consistent with both their PPI and learning defects, cortical pyramidal neurons from Upf3b-null mice display deficient dendritic spine maturation in vivo. In addition, neural stem cells from Upf3b-null mice have impaired ability to undergo differentiation and require prolonged culture to give rise to functional neurons with electrical activity. RNA sequencing (RNAseq) analysis of the frontal cortex identified UPF3B-regulated RNAs, including direct NMD target transcripts encoding proteins with known functions in neural differentiation, maturation and disease. We suggest Upf3b-null mice serve as a novel model system to decipher cellular and molecular defects underlying ID and neurodevelopmental disorders

Contrasting Patterns of Damage and Recovery in Logged Amazon Forests From Small Footprint LiDAR Data

Tropical forests ecosystems respond dynamically to climate variability and disturbances on time scales of minutes to millennia. To date, our knowledge of disturbance and recovery processes in tropical forests is derived almost exclusively from networks of forest inventory plots. These plots typically sample small areas (less than or equal to 1 ha) in conservation units that are protected from logging and fire. Amazon forests with frequent disturbances from human activity remain under-studied. Ongoing negotiations on REDD+ (Reducing Emissions from Deforestation and Forest Degradation plus enhancing forest carbon stocks) have placed additional emphasis on identifying degraded forests and quantifying changing carbon stocks in both degraded and intact tropical forests. We evaluated patterns of forest disturbance and recovery at four -1000 ha sites in the Brazilian Amazon using small footprint LiDAR data and coincident field measurements. Large area coverage with airborne LiDAR data in 2011-2012 included logged and unmanaged areas in Cotriguacu (Mato Grosso), Fiona do Jamari (Rondonia), and Floresta Estadual do Antimary (Acre), and unmanaged forest within Reserva Ducke (Amazonas). Logging infrastructure (skid trails, log decks, and roads) was identified using LiDAR returns from understory vegetation and validated based on field data. At each logged site, canopy gaps from logging activity and LiDAR metrics of canopy heights were used to quantify differences in forest structure between logged and unlogged areas. Contrasting patterns of harvesting operations and canopy damages at the three logged sites reflect different levels of pre-harvest planning (i.e., informal logging compared to state or national logging concessions), harvest intensity, and site conditions. Finally, we used multi-temporal LiDAR data from two sites, Reserva Ducke (2009, 2012) and Antimary (2010, 2011), to evaluate gap phase dynamics in unmanaged forest areas. The rates and patterns of canopy gap formation at these sites illustrate potential issues for separating logging damages from natural forest disturbances over longer time scales. Multi-temporal airborne LiDAR data and coincident field measurements provide complementary perspectives on disturbance and recovery processes in intact and degraded Amazon forests. Compared to forest inventory plots, the large size of each individual site permitted analyses of landscape-scale processes that would require extremely high investments to study using traditional forest inventory methods

Multi-state models and arthroplasty histories after unilateral total hip arthroplasties: Introducing the Summary Notation for Arthroplasty Histories

Background and purpose: An increasing number of patients have several joint replacement procedures during their lifetime. We investigated the use and suitability of multi-state model techniques in providing a more comprehensive analysis and description of complex arthroplasty histories held in arthroplasty registries than are allowed for with traditional survival methods. Patients and methods: We obtained data from the Australian Orthopaedic Association National Joint Replacement Registry on patients (n = 84,759) who had undergone a total hip arthroplasty for osteoarthritis in the period 2002–2008. We set up a multi-state model where patients were followed from their first recorded arthroplasty to several possible states: revision of first arthroplasty, either a hip or knee as second arthroplasty, revision of the second arthroplasty, and death. The Summary Notation for Arthroplasty Histories (SNAH) was developed in order to help to manage and analyze this type of data. Results: At the end of the study period, 12% of the 84,759 patients had received a second hip, 3 times as many as had received a knee. The estimated probabilities of having received a second arthroplasty decreased with age. Males had a lower transition rate for receiving a second arthroplasty, but a higher mortality rate. Interpretation: Multi-state models in combination with SNAH codes are well suited to the management and analysis of arthroplasty registry data on patients who experience multiple joint procedures over time. We found differences in the progression of joint replacement procedures after the initial total hip arthroplasty regarding type of joint, age, and sex.Marianne H Gillam, Philip Ryan, Amy Salter, Stephen E Grave

Long-term exposure to outdoor air pollution and the incidence of chronic obstructive pulmonary disease in a national English cohort.

OBJECTIVES: The role of outdoor air pollution in the incidence of chronic obstructive pulmonary disease (COPD) remains unclear. We investigated this question using a large, nationally representative cohort based on primary care records linked to hospital admissions. METHODS: A cohort of 812 063 patients aged 40-89 years registered with 205 English general practices in 2002 without a COPD diagnosis was followed from 2003 to 2007. First COPD diagnoses recorded either by a general practitioner (GP) or on admission to hospital were identified. Annual average concentrations in 2002 for particulate matter with an aerodynamic diameter <10 µm (PM10) and <2.5 µm (PM2.5), nitrogen dioxide (NO2), ozone and sulfur dioxide (SO2) at 1 km(2) resolution were estimated from emission-based dispersion models. Hazard ratios (HRs) per interquartile range change were estimated from Cox models adjusting for age, sex, smoking, body mass index and area-level deprivation. RESULTS: 16 034 participants (1.92%) received a COPD diagnosis from their GP and 2910 participants (0.35%) were admitted to hospital for COPD. After adjustment, HRs for GP recorded COPD and PM10, PM2.5 and NO2 were close to unity, positive for SO2 (HR=1.07 (95% CI 1.03 to 1.11) per 2.2 µg/m(3)) and negative for ozone (HR=0.94 (0.89 to 1.00) per 3 µg/m(3)). For admissions HRs for PM2.5 and NO2 remained positive (HRs=1.05 (0.98 to 1.13) and 1.06 (0.98 to 1.15) per 1.9 µg/m(3) and 10.7 µg/m(3), respectively). CONCLUSIONS: This large population-based cohort study found limited, inconclusive evidence for associations between air pollution and COPD incidence. Further work, utilising improved estimates of air pollution over time and enhanced socioeconomic indicators, is required to clarify the association between air pollution and COPD incidence

Takeaway meal consumption and risk markers for coronary heart disease, type 2 diabetes and obesity in children aged 9-10 years: a cross-sectional study.

OBJECTIVE: To investigate associations between takeaway meal consumption and risk markers for coronary heart disease, type 2 diabetes and obesity risk markers in children. DESIGN: A cross-sectional, school-based observational study. SETTING: 85 primary schools across London, Birmingham and Leicester. PARTICIPANTS: 1948 UK primary school children in year 5, aged 9-10 years. MAIN OUTCOME MEASURES: Children reported their frequency of takeaway meal consumption, completed a 24-hour dietary recall, had physical measurements and provided a fasting blood sample. RESULTS: Among 1948 participants with complete data, 499 (26%) never/hardly ever consumed a takeaway meal, 894 (46%) did so <1/week and 555 (28%) did ≥1/week. In models adjusted for age, sex, month, school, ethnicity and socioeconomic status, more frequent takeaway meal consumption was associated with higher dietary intakes of energy, fat % energy and saturated fat % energy and higher energy density (all P trend <0.001) and lower starch, protein and micronutrient intakes (all P trend <0.05). A higher frequency of takeaway meal consumption was associated with higher serum total cholesterol and low-density lipoprotein (LDL) cholesterol (P trend=0.04, 0.01, respectively); children eating a takeaway meal ≥1/week had total cholesterol and LDL cholesterol 0.09 mmol/L (95% CI 0.01 to 0.18) and 0.10 mmol/L (95% CI 0.02 to 0.18) higher respectively than children never/hardly ever eating a takeaway meal; their fat mass index was also higher. CONCLUSIONS: More frequent takeaway meal consumption in children was associated with unhealthy dietary nutrient intake patterns and potentially with adverse longer term consequences for obesity and coronary heart disease risk

Regular breakfast consumption and type 2 diabetes risk markers in 9- to 10-year-old children in the child heart and health study in England (CHASE): a cross-sectional analysis.

BACKGROUND: Regular breakfast consumption may protect against type 2 diabetes risk in adults but little is known about its influence on type 2 diabetes risk markers in children. We investigated the associations between breakfast consumption (frequency and content) and risk markers for type 2 diabetes (particularly insulin resistance and glycaemia) and cardiovascular disease in children. METHODS AND FINDINGS: We conducted a cross-sectional study of 4,116 UK primary school children aged 9-10 years. Participants provided information on breakfast frequency, had measurements of body composition, and gave fasting blood samples for measurements of blood lipids, insulin, glucose, and glycated haemoglobin (HbA1c). A subgroup of 2,004 children also completed a 24-hour dietary recall. Among 4,116 children studied, 3,056 (74%) ate breakfast daily, 450 (11%) most days, 372 (9%) some days, and 238 (6%) not usually. Graded associations between breakfast frequency and risk markers were observed; children who reported not usually having breakfast had higher fasting insulin (percent difference 26.4%, 95% CI 16.6%-37.0%), insulin resistance (percent difference 26.7%, 95% CI 17.0%-37.2%), HbA1c (percent difference 1.2%, 95% CI 0.4%-2.0%), glucose (percent difference 1.0%, 95% CI 0.0%-2.0%), and urate (percent difference 6%, 95% CI 3%-10%) than those who reported having breakfast daily; these differences were little affected by adjustment for adiposity, socioeconomic status, and physical activity levels. When the higher levels of triglyceride, systolic blood pressure, and C-reactive protein for those who usually did not eat breakfast relative to those who ate breakfast daily were adjusted for adiposity, the differences were no longer significant. Children eating a high fibre cereal breakfast had lower insulin resistance than those eating other breakfast types (p for heterogeneity <0.01). Differences in nutrient intakes between breakfast frequency groups did not account for the differences in type 2 diabetes markers. CONCLUSIONS: Children who ate breakfast daily, particularly a high fibre cereal breakfast, had a more favourable type 2 diabetes risk profile. Trials are needed to quantify the protective effect of breakfast on emerging type 2 diabetes risk. Please see later in the article for the Editors' Summary

Metabolic rate throughout the annual cycle reveals the demands of an Arctic existence in Great Cormorants

Aquatic endotherms living in polar regions are faced with a multitude of challenges, including low air and water temperatures and low illumination, especially in winter. Like other endotherms from cold environments, Great Cormorants (Phalacrocorax carbo) living in Arctic waters were hypothesized to respond to these challenges through combination of high daily rate of energy expenditure (DEE) and high food requirements, which are met by a high rate of catch per unit effort (CPUE). CPUE has previously been shown in Great Cormorants to be the highest of any diving bird. In the present study, we tested this hypothesis by making the first measurements of DEE and foraging activity of Arctic-dwelling Great Cormorants throughout the annual cycle. We demonstrate that, in fact, Great Cormorants have surprisingly low rates of DEE. This low DEE is attributed primarily to very low levels of foraging activity, particularly during winter, when the cormorants spent only 2% of their day submerged. Such a low level of foraging activity can only be sustained through consistently high foraging performance. We demonstrate that Great Cormorants have one of the highest recorded CPUEs for a diving predator; 18.6 g per minute submerged (95% prediction interval 13.0-24.2 g/min) during winter. Temporal variation in CPUE was investigated, and highest CPUE was associated with long days and shallow diving depths. The effect of day length is attributed to seasonal variation in prey abundance. Shallow diving leads to high CPUE because less time is spent swimming between the surface and the benthic zone where foraging occurs. Our study demonstrates the importance of obtaining accurate measurements of physiology and behavior from free-living animals when attempting to understand their ecology

A copula model for marked point processes

The final publication (Diao, Liqun, Richard J. Cook, and Ker-Ai Lee. (2013) A copula model for marked point processes. Lifetime Data Analysis, 19(4): 463-489) is available at Springer via http://dx.doi.org/10.1007/s10985-013-9259-3Many chronic diseases feature recurring clinically important events. In addition, however, there often exists a random variable which is realized upon the occurrence of each event reflecting the severity of the event, a cost associated with it, or possibly a short term response indicating the effect of a therapeutic intervention. We describe a novel model for a marked point process which incorporates a dependence between continuous marks and the event process through the use of a copula function. The copula formulation ensures that event times can be modeled by any intensity function for point processes, and any multivariate model can be specified for the continuous marks. The relative efficiency of joint versus separate analyses of the event times and the marks is examined through simulation under random censoring. An application to data from a recent trial in transfusion medicine is given for illustration.Natural Sciences and Engineering Research Council of Canada (RGPIN 155849); Canadian Institutes for Health Research (FRN 13887); Canada Research Chair (Tier 1) – CIHR funded (950-226626

Normal cervical changes in parous women during the second half of pregnancy - a prospective, longitudinal ultrasound study

OBJECTIVE: To determine what constitutes normal cervical changes during the second half of pregnancy in parous women delivering at term. DESIGN: The study comprises 21 healthy, pregnant parous women who all gave birth at term. They were examined with transvaginal ultrasound every two weeks from 24 gestational weeks until delivery. Cervical length and width were measured. The inner cervical os was assessed as being closed or open, the length and width of any opening were measured, and dynamic cervical changes (i.e. opening and closing of the inner cervical os during examination) were noted. RESULTS: Median cervical length was 41 mm (range 26-55) at the first examination and 29 mm (range 8-56) at the last examination. The corresponding figures for cervical width were 38 mm (range 29-47) and 46 mm (range 38-64). Cervical length decreased in 18 women but remained unchanged in three. Three patterns of change in cervical length were observed: in 12 women there was a steady, continuous decrease in cervical length (median decrease rate 1.1 mm/week, range 0.6-2.4); in four women the decrease rate accelerated towards the end of pregnancy, the median decrease rate after the change being 3.0 mm/week (range 1.5-4.8); and in two women there was a sudden drop in cervical length at term. Cervical width increased in 16 women but remained unchanged in five. Two patterns of change in cervical width were seen: 14 women manifested a steady continuous increase in cervical width (median 0.8 mm/week, range 0.4-1.8); in two women the increase rate accelerated from around 34 gestational weeks, the increase rate after the change being 4.1 and 5.9 mm/week, respectively. Opening of the internal cervical os was observed at least once in 11 (52%) women and was seen as early as at 24 and 25 gestational weeks in two women. The opening was always V-shaped (median length 6 mm, range 4-17; median width 7 mm, range 3-20). Dynamic changes of the internal cervical os were seen in three women (14%) at 25, 30 and 41 gestational weeks, respectively. CONCLUSION: The cervix of parous women decreases in length and increases in width from midpregnancy to term, but the pattern of change varies between individuals. Knowledge of the different patterns of normal change forms the basis of transvaginal ultrasound studies of pathological cervical changes during pregnancy

Effects of Grassland Management Practices on Ant Functional Groups in Central North America

Tallgrass prairies of central North America have experienced disturbances including fire and grazing for millennia. Little is known about the effects of these disturbances on prairie ants, even though ants are thought to play major roles in ecosystem maintenance. We implemented three management treatments on remnant and restored grassland tracts in the central U.S., and compared the effects of treatment on abundance of ant functional groups. Management treatments were: (1) patch-burn graze—rotational burning of three spatially distinct patches within a fenced tract, and growing-season cattle grazing; (2) graze-and-burn—burning entire tract every 3 years, and growing-season cattle grazing, and (3) burn-only—burning entire tract every 3 years, but no cattle grazing. Ant species were classified into one of four functional groups. Opportunist ants and the dominant ant species, Formica montana, were more abundant in burn-only tracts than tracts managed with either of the grazing treatments. Generalists were more abundant in graze-and-burn tracts than in burn-only tracts. Abundance of F. montana was negatively associated with pre-treatment time since fire, whereas generalist ant abundance was positively associated. F. montanawere more abundant in restored tracts than remnants, whereas the opposite was true for subdominants and opportunists. In summary, abundance of the dominant F. montana increased in response to intense disturbances that were followed by quick recovery of plant biomass. Generalist ant abundance decreased in response to those disturbances, which we attribute to the effects of competitive dominance of F. montana upon the generalists