The analysis of SATS results as a measure of pupil progress across educational transitions

Within any Educational System the transition of pupils from one stage to the next, and often the associated transition from one educational establishment to another, is an area of interest for educational establishments, educationalists and educational authorities due to the effects of this movement on pupil progress, their academic achievement and performance measures for schools. The National Curriculum Assessments (NCA) are used in England as a nationally administered examination to evaluate pupil progress and academic achievement at the transition from one Key Stage to another. Also within England different schools can have differently aged cohorts, for example Primary Schools cover ages 4 to 11 years whereas Infant Schools cover ages 4 to 7 years and Junior Schools 7 to 11 years. This investigation has examined the significance of type of primary school (i.e., all-age primary, 4 to 11 years, versus junior, 7 to 11 years) for achievement at age 11 years. Using national statistics, it was shown that junior and primary schools perform equivalently in terms of academic achievement at the end of the pupils’ time in the schools but primary schools seem to outperform junior schools in terms of the improvement in the pupils’ ability (value added) during their time in Key Stage 2. This work has shown that on average a junior school will have a lower value added score at Key Stage 2 to equivalently performing primary schools and that this difference, whilst small, is both statistically, and in terms of league table position, significant. Also, the data were compared to the much smaller group of schools which provide education from Key Stage 1 through to Key Stage 4 and beyond. These schools showed the same rate of progress (value added) through Key Stages 1 and 2 as the general population of schools but with lower points scores per student

The analysis of SATS results as a measure of pupil progress across educational transitions

Within any Educational System the transition of pupils from one stage to the next, and often the associated transition from one educational establishment to another, is an area of interest for educational establishments, educationalists and educational authorities due to the effects of this movement on pupil progress, their academic achievement and performance measures for schools. The National Curriculum Assessments (NCA) are used in England as a nationally administered examination to evaluate pupil progress and academic achievement at the transition from one Key Stage to another. Also within England different schools can have differently aged cohorts, for example Primary Schools cover ages 4 to 11 years whereas Infant Schools cover ages 4 to 7 years and Junior Schools 7 to 11 years. This investigation has examined the significance of type of primary school (i.e., all-age primary, 4 to 11 years, versus junior, 7 to 11 years) for achievement at age 11 years. Using national statistics, it was shown that junior and primary schools perform equivalently in terms of academic achievement at the end of the pupils’ time in the schools but primary schools seem to outperform junior schools in terms of the improvement in the pupils’ ability (value added) during their time in Key Stage 2. This work has shown that on average a junior school will have a lower value added score at Key Stage 2 to equivalently performing primary schools and that this difference, whilst small, is both statistically, and in terms of league table position, significant. Also, the data were compared to the much smaller group of schools which provide education from Key Stage 1 through to Key Stage 4 and beyond. These schools showed the same rate of progress (value added) through Key Stages 1 and 2 as the general population of schools but with lower points scores per student

Laser Capture and Deep Sequencing Reveals the Transcriptomic Programmes Regulating the Onset of Pancreas and Liver Differentiation in Human Embryos.

To interrogate the alternative fates of pancreas and liver in the earliest stages of human organogenesis, we developed laser capture, RNA amplification, and computational analysis of deep sequencing. Pancreas-enriched gene expression was less conserved between human and mouse than for liver. The dorsal pancreatic bud was enriched for components of Notch, Wnt, BMP, and FGF signaling, almost all genes known to cause pancreatic agenesis or hypoplasia, and over 30 unexplored transcription factors. SOX9 and RORA were imputed as key regulators in pancreas compared with EP300, HNF4A, and FOXA family members in liver. Analyses implied that current in vitro human stem cell differentiation follows a dorsal rather than a ventral pancreatic program and pointed to additional factors for hepatic differentiation. In summary, we provide the transcriptional codes regulating the start of human liver and pancreas development to facilitate stem cell research and clinical interpretation without inter-species extrapolation.This project received support from the UK Medical Research Council (MRC) (R.E.J. was a clinical research training fellow; additional funding from MR/L009986/1 to N.B. and N.A.H.; and MR/J003352/1 to K.P.H.), the Academy of Medical Sciences (supported by Wellcome Trust, MRC, British Heart Foundation, Arthritis Research UK, the Royal College of Physicians and Diabetes UK) (R.E.J.), the Society for Endocrinology (R.E.J.), the Wellcome Trust (N.A.H. was a senior fellow in clinical science, 088566; additional support from grant 105610/Z/14/Z), and the British Council and JDRF (14BX15NHBG to N.A.H.)

Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes

Background & Aims: Hepatocyte-like cells (HLCs), differentiated from pluripotent stem cells by the use of soluble factors, can model human liver function and toxicity. However, at present HLC maturity and whether any deficit represents a true fetal state or aberrant differentiation is unclear and compounded by comparison to potentially deteriorated adult hepatocytes. Therefore, we generated HLCs from multiple lineages, using two different protocols, for direct comparison with fresh fetal and adult hepatocytes. Methods: Protocols were developed for robust differentiation. Multiple transcript, protein and functional analyses compared HLCs to fresh human fetal and adult hepatocytes. Results: HLCs were comparable to those of other laboratories by multiple parameters. Transcriptional changes during differentiation mimicked human embryogenesis and showed more similarity to pericentral than periportal hepatocytes. Unbiased proteomics demonstrated greater proximity to liver than 30 other human organs or tissues. However, by comparison to fresh material, HLC maturity was proven by transcript, protein and function to be fetal-like and short of the adult phenotype. The expression of 81% phase 1 enzymes in HLCs was significantly upregulated and half were statistically not different from fetal hepatocytes. HLCs secreted albumin and metabolized testosterone (CYP3A) and dextrorphan (CYP2D6) like fetal hepatocytes. In seven bespoke tests, devised by principal components analysis to distinguish fetal from adult hepatocytes, HLCs from two different source laboratories consistently demonstrated fetal characteristics. Conclusions: HLCs from different sources are broadly comparable with unbiased proteomic evidence for faithful differentiation down the liver lineage. This current phenotype mimics human fetal rather than adult hepatocytes

Pluripotency and X chromosome dynamics revealed in pig pre-gastrulating embryos by single cell analysis.

High-resolution molecular programmes delineating the cellular foundations of mammalian embryogenesis have emerged recently. Similar analysis of human embryos is limited to pre-implantation stages, since early post-implantation embryos are largely inaccessible. Notwithstanding, we previously suggested conserved principles of pig and human early development. For further insight on pluripotent states and lineage delineation, we analysed pig embryos at single cell resolution. Here we show progressive segregation of inner cell mass and trophectoderm in early blastocysts, and of epiblast and hypoblast in late blastocysts. We show that following an emergent short naive pluripotent signature in early embryos, there is a protracted appearance of a primed signature in advanced embryonic stages. Dosage compensation with respect to the X-chromosome in females is attained via X-inactivation in late epiblasts. Detailed human-pig comparison is a basis towards comprehending early human development and a foundation for further studies of human pluripotent stem cell differentiation in pig interspecies chimeras

Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments

This work is licensed under a Creative Commons Attribution 4.0 International License.(−)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). “Body” and “tail” interactions with opioid receptors (a subset of Portoghese’s message-address theory) were used for molecular modeling and simulations, where the “address” can be considered the “body” of the hydromorphone molecule and the “message” delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.NIDA grant P30 DA13429NIDA grant DA039997NIDA grant DA018151NIDA grant DA035857NIDA grant DA047574NIH Intramural Research Programs of the National Institute on Drug AbuseNational Institute of Alcohol Abuse and AlcoholismNIH Intramural Research Programs of the National Institute on Drug AbuseNIH Intramural Research Program through the Center for Information TechnologyNIH Intramural Research Programs of the National Institute on Drug Abus

Principles of early human development and germ cell program from conserved model systems

Human primordial germ cells (hPGCs), the precursors of sperm and eggs, originate during week 2-3 of early postimplantation development(1). Using in vitro models of hPGC induction(2-4), recent studies suggest striking mechanistic differences in specification of human and mouse PGCs(5). This may partly be due to the divergence in their pluripotency networks, and early postimplantation development(6-8). Since early human embryos are inaccessible for direct studies, we considered alternatives, including porcine embryos that, as in humans, develop as bilaminar embryonic discs. Here we show that porcine PGCs (pPGCs) originate from the posterior pre-primitive streak competent epiblast by sequential upregulation of SOX17 and BLIMP1 in response to WNT and BMP signalling. Together with human and monkey in vitro models simulating peri-gastrulation development, we show conserved principles for epiblast development for competency for PGC fate, followed by initiation of the epigenetic program(9-11), regulated by a balanced SOX17–BLIMP1 gene dosage. Our combinatorial approach using human, porcine and monkey in vivo and in vitro models, provides synthetic insights on early human development

Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders

From Springer Nature via Jisc Publications RouterHistory: received 2019-10-04, accepted 2020-06-18, registration 2020-06-24, pub-electronic 2020-08-06, online 2020-08-06, collection 2020-12Publication status: PublishedFunder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265; Grant(s): CRTF, PhD studentship, MR/J003352/1, MR/L009986/1, MR/L009986/1, MR/S036121/1, MR/000638/1Funder: Academy of Medical Sciences; doi: https://doi.org/10.13039/501100000691; Grant(s): Lecturer starter grantFunder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440; Grant(s): 088566, 097820, 105610Abstract: How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partition into discrete states. Key developmental gene sets are actively repressed outside of the appropriate organ without obvious bivalency. Candidate enhancers, functional in zebrafish, allow imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allows correlation to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for investigating normal and abnormal human development