The direct detection of drug-protein interactions in living cells is a major challenge in drug discovery research. Recently, we introduced an approach termed thermal proteome profiling (TPP), which ...enables the monitoring of changes in protein thermal stability across the proteome using quantitative mass spectrometry. We determined the intracellular thermal profiles for up to 7,000 proteins, and by comparing profiles derived from cultured mammalian cells in the presence or absence of a drug we showed that it was possible to identify direct and indirect targets of drugs in living cells in an unbiased manner. Here we demonstrate the complete workflow using the histone deacetylase inhibitor panobinostat. The key to this approach is the use of isobaric tandem mass tag 10-plex (TMT10) reagents to label digested protein samples corresponding to each temperature point in the melting curve so that the samples can be analyzed by multiplexed quantitative mass spectrometry. Important steps in the bioinformatic analysis include data normalization, melting curve fitting and statistical significance determination of compound concentration-dependent changes in protein stability. All analysis tools are made freely available as R and Python packages. The workflow can be completed in 2 weeks.
To assess the clinical course and genotype-phenotype correlations in patients with selenoprotein-related myopathy (SEPN1-RM) due to selenoprotein N1 gene (SEPN1) mutations for a retrospective ...cross-sectional study.
Forty-one patients aged 1-60 years were included. Clinical data including scoliosis, respiratory function, and growth measurements were collected by case note review.
Mean age at onset was 2.7 years, ranging from birth to the second decade of life. All but 2 remained independently ambulant: one lost ambulation at age 5 years and another in his late 50s. The mean age of starting nocturnal noninvasive ventilation (NIV) was 13.9 years. One child required full-time NIV at the age of 1 year while in 2 cases NIV was started at 33 years. Two patients died from respiratory failure at the age of 10 and 22 years, respectively. The mean age at scoliosis onset was 10 years, in most cases preceded by rigidity of the spine. Fourteen patients had successful spinal surgery (mean age 13.9 years). Twenty-one were underweight; however, overt feeding difficulties were not a feature.
This study describes the largest population affected by SEPN1-RM reported so far. Our findings show that the spectrum of severity is wider than previously reported. Respiratory insufficiency generally develops by 14 years but may occur as early as in infancy or not until the fourth decade. Motor abilities remain essentially static over time even in patients with early presentation. Most adult patients remain ambulant and fully employed.
Accurate information on the growth rates of fish is crucial for fisheries stock assessment and management. Empirical life history parameters (von Bertalanffy growth) are widely fitted to ...cross-sectional size-at-age data sampled from fish populations. This method often assumes that environmental factors affecting growth remain constant over time. The current study utilized longitudinal life history information contained in otoliths from 412 juveniles and adults of gilthead seabream, Sparus aurata, a commercially important species fished and farmed throughout the Mediterranean. Historical annual growth rates over 11 consecutive years (2002-2012) in the Gulf of Lions (NW Mediterranean) were reconstructed to investigate the effect of temperature variations on the annual growth of this fish. S. aurata growth was modelled linearly as the relationship between otolith size at year t against otolith size at the previous year t-1. The effect of temperature on growth was modelled with linear mixed effects models and a simplified linear model to be implemented in a cohort Integral Projection Model (cIPM). The cIPM was used to project S. aurata growth, year to year, under different temperature scenarios. Our results determined current increasing summer temperatures to have a negative effect on S. aurata annual growth in the Gulf of Lions. They suggest that global warming already has and will further have a significant impact on S. aurata size-at-age, with important implications for age-structured stock assessments and reference points used in fisheries.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Phospholipase A2 associated neurodegeneration (PLAN) is a major phenotype of autosomal recessive Neurodegeneration with Brain Iron Accumulation (NBIA). We describe the clinical phenotypes, ...neuroimaging features and PLA2G6 mutations in 5 children, of whom 4 presented with infantile neuroaxonal dystrophy (INAD). One other patient was diagnosed with the onset of PLAN in childhood, and our report highlights the diagnostic challenges associated with this atypical PLAN subtype. In this series, the neuroradiological relevance of classical PLAN features as well as apparent claval hypertrophy’ is explored. Novel PLA2G6 mutations were identified in all patients. PLAN should be considered not only in patients presenting with a classic INAD phenotype but also in older patients presenting later in childhood with non-specific progressive neurological features including social communication difficulties, gait disturbance, dyspraxia, neuropsychiatric symptoms and extrapyramidal motor features.
ILS is a rare lesion that has a different management from the more common "acoustic" schwannoma. To date, only 137 cases have been reported. We present a classification scheme based on labyrinthine ...anatomy to describe and localize these lesions. Treatment and prognosis hinge on the appropriate localization of these tumors; thus, a concise terminology that can be used by both the otolaryngologist and radiology communities is desirable.
After approval of the institutional review board, a retrospective study of all patients with the diagnosis of ILS imaged between 1996 and 2010 was performed. Clinical and imaging data were collected. Patients were imaged with thin-section high-resolution T2 and contrast-enhanced MR imaging.
There were 45 patients with a diagnosis of ILS. Forty-three had complete histories. There were 18 male and 25 female patients with an age range of 21-78 years with a mean age of 53 years. The most common presenting symptom was progressive sensorineural hearing loss. Lesions were characterized on the basis of their location. Intracochlear was most common (14/45) followed by transmodiolar (13/45), intravestibular (7/45), vestibulocochlear (5/45), transmacular (4/45), and transotic (2/45). Sixteen patients underwent surgical resection. The remaining patients were followed clinically and by serial MR imaging.
ILS is an uncommon but under-reported tumor. We characterized the MR imaging appearance of these tumors by using high-resolution techniques. In addition, an anatomically based classification system is presented that will help the radiologist accurately describe ILS within the inner ear and help the surgeon determine which tumors are potential surgical candidates.
Summary Background In 2000, world leaders agreed on the Millennium Development Goals (MDGs). MDG 4 called for a two-thirds reduction in the under-5 mortality rate between 1990 and 2015. We aimed to ...estimate levels and trends in under-5 mortality for 195 countries from 1990 to 2015 to assess MDG 4 achievement and then intended to project how various post-2015 targets and observed rates of change will affect the burden of under-5 deaths from 2016 to 2030. Methods We updated the UN Inter-agency Group for Child Mortality Estimation (UN IGME) database with 5700 country-year datapoints. As of July, 2015, the database contains about 17 000 country-year datapoints for mortality of children younger than 5 years for 195 countries, and includes all available nationally-representative data from vital registration systems, population censuses, household surveys, and sample registration systems. We used these data to generate estimates, with uncertainty intervals, of under-5 (age 0–4 years) mortality using a Bayesian B-spline bias-reduction model (B3 model). This model includes a data model to adjust for systematic biases associated with different types of data sources. To provide insights into the global and regional burden of under-5 deaths associated with post-2015 targets, we constructed five scenario-based projections for under-5 mortality from 2016 to 2030 and estimated national, regional, and global under-5 mortality rates up to 2030 for each scenario. Results The global under-5 mortality rate has fallen from 90·6 deaths per 1000 livebirths (90% uncertainty interval 89·3–92·2) in 1990 to 42·5 (40·9–45·6) in 2015. During the same period, the annual number of under-5 deaths worldwide dropped from 12·7 million (12·6 million–13·0 million) to 5·9 million (5·7 million–6·4 million). The global under-5 mortality rate reduced by 53% (50–55%) in the past 25 years and therefore missed the MDG 4 target. Based on point estimates, two regions—east Asia and the Pacific, and Latin America and the Caribbean—achieved the MDG 4 target. 62 countries achieved the MDG 4 target, of which 24 were low-income and lower-middle income countries. Between 2016 and 2030, 94·4 million children are projected to die before the age of 5 years if the 2015 mortality rate remains constant in each country, and 68·8 million would die if each country continues to reduce its mortality rate at the pace estimated from 2000 to 2015. If all countries achieve the Sustainable Development Goal of an under-5 mortality rate of 25 or fewer deaths per 1000 livebirths by 2030, we project 56·0 million deaths by 2030. About two-thirds of all sub-Saharan African countries need to accelerate progress to achieve this target. Interpretation Despite substantial progress in reducing child mortality, concerted efforts remain necessary to avoid preventable under-5 deaths in the coming years and to accelerate progress in improving child survival further. Urgent actions are needed most in the regions and countries with high under-5 mortality rates, particularly those in sub-Saharan Africa and south Asia. Funding None.
This study of temporal trends in mortality among extremely premature infants receiving care in U.S. centers showed declines in overall mortality and in deaths from pulmonary causes, immaturity, ...infection, and CNS injury. Deaths from necrotizing enterocolitis increased.
Although survival among premature infants has improved, prematurity is a leading contributor to neonatal mortality in the United States.
1
Approximately one in four extremely premature infants born at 22 to 28 weeks of gestation does not survive the birth hospitalization; mortality rates decrease with each additional week of completed gestation.
2
Historically, most extremely premature infants died within a few days after birth.
3
–
5
Among extremely-low-birth-weight infants born at centers in the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between 1993 and 1997, immaturity was the leading cause of death within 12 hours after birth, and . . .
Studies in high-income countries show that despite the positive association of weight with socioeconomic position at birth, an inverse socioeconomic gradient in overweight (OW) appears later in ...childhood. The objectives were to understand the natural history of socioeconomic inequalities in weight, height and body mass index (BMI), by investigating their associations with maternal educational level between birth and 5 years, separately in boys and girls.
A published work of growth modelling between birth and 5 years allowed us to calculate predicted weight, height and BMI at 1 month, 6 months, 1, 3 and 5 years for 1735 children from the French EDEN mother-child cohort. Associations between maternal education and predicted measures of body size were analysed with marginal linear and logistic models, stratified by sex.
In girls, despite a positive association between maternal education and birthweight, an inverse socioeconomic gradient was observed as early as 1 month for BMI. Girls whose mothers had low education levels were shorter on the whole than their counterparts with better-educated mothers, despite their similar weights. In boys, no socioeconomic gradient in BMI was observed at any age, including birth, but positive associations were found as early as 1 month for both weight and height.
The emergence of an inverse socioeconomic gradient in BMI and OW apparently results from a complex pattern of socioeconomic inequalities in weight and height from 1 month onwards. The very start of life thus appears to be an important window of opportunity for addressing socioeconomic inequalities in growth.
Early eating patterns and behaviors can determine later eating habits and food preferences and they have been related to the development of childhood overweight and obesity. We aimed to identify ...patterns of feeding in the first year of life and to examine their associations with family characteristics.
Our analysis included 1004 infants from the EDEN mother-child cohort. Feeding practices were assessed through maternal self-report at birth, 4, 8 and 12 months. Principal component analysis was applied to derive patterns from breastfeeding duration, age at complementary food (CF) introduction and type of food used at 1 year. Associations between patterns and family characteristics were analyzed by linear regressions.
The main source of variability in infant feeding was characterized by a pattern labeled 'late CF introduction and use of ready-prepared baby foods'. Older, more educated, primiparous women with high monthly income ranked high on this pattern. The second pattern, labeled 'longer breastfeeding, late CF introduction and use of home-made foods' was the closest to infant feeding guidelines. Mothers ranking high on this pattern were older and more educated. The third pattern, labeled 'use of adults' foods' suggests a less age-specific diet for the infants. Mothers ranking high on this pattern were often younger and multiparous. Recruitment center was related to all patterns.
Not only maternal education level and age, but also parity and region are important contributors to the variability in patterns. Further studies are needed to describe associations between these patterns and infant growth and later food preferences.
Summary Background There is little information on country trends in the complete distributions of children's anthropometric status, which are needed to assess all levels of mild to severe ...undernutrition. We aimed to estimate trends in the distributions of children's anthropometric status and assess progress towards the Millennium Development Goal 1 (MDG 1) target of halving the prevalence of weight-for-age Z score (WAZ) below −2 between 1990 and 2015 or reaching a prevalence of 2·3% or lower. Methods We collated population-representative data on height-for-age Z score (HAZ) and WAZ calculated with the 2006 WHO child growth standards. Our data sources were health and nutrition surveys, summary statistics from the WHO Global Database on Child Growth and Malnutrition, and summary statistics from reports of other national and international agencies. We used a Bayesian hierarchical mixture model to estimate Z -score distributions. We quantified the uncertainty of our estimates, assessed their validity, compared their performance to alternative models, and assessed sensitivity to key modelling choices. Findings In developing countries, mean HAZ improved from −1·86 (95% uncertainty interval −2·01 to −1·72) in 1985 to −1·16 (–1·29 to −1·04) in 2011; mean WAZ improved from −1·31 (–1·41 to −1·20) to −0·84 (–0·93 to −0·74). Over this period, prevalences of moderate-and-severe stunting declined from 47·2% (44·0 to 50·3) to 29·9% (27·1 to 32·9) and underweight from 30·1% (26·7 to 33·3) to 19·4% (16·5 to 22·2). The largest absolute improvements were in Asia and the largest relative reductions in prevalence in southern and tropical Latin America. Anthropometric status worsened in sub-Saharan Africa until the late 1990s and improved thereafter. In 2011, 314 (296 to 331) million children younger than 5 years were mildly, moderately, or severely stunted and 258 (240 to 274) million were mildly, moderately, or severely underweight. Developing countries as a whole have less than a 5% chance of meeting the MDG 1 target; but 61 of these 141 countries have a 50–100% chance. Interpretation Macroeconomic shocks, structural adjustment, and trade policy reforms in the 1980s and 1990s might have been responsible for worsening child nutritional status in sub-Saharan Africa. Further progress in the improvement of children's growth and nutrition needs equitable economic growth and investment in pro-poor food and primary care programmes, especially relevant in the context of the global economic crisis. Funding The Bill & Melinda Gates Foundation and the UK Medical Research Council.
PDF
