Behavioural cloning of teachers for automatic homework selection

© Springer Nature Switzerland AG 2019. We describe a machine-learning system for supporting teachers through the selection of homework assignments. Our system uses behavioural cloning of teacher activity to generate personalised homework assignments for students. Classroom use is then supported through additional mechanisms to combine these predictions into group assignments. We train and evaluate our system against 50,065 homework assignments collected over two years by the Isaac Physics platform. We use baseline policies incorporating expert curriculum knowledge for evaluation and find that our technique improves on the strongest baseline policy by 18.5% in Year 1 and by 13.3% in Year 2.Cambridge Assessmen

Diamorphine pharmacokinetics and conversion factor estimates for intranasal diamorphine in paediatric breakthrough pain:systematic review

BACKGROUND: Intranasal diamorphine is a potential treatment for breakthrough pain but few paediatric data are available to assist dose estimation. AIM: To determine an intranasal diamorphine dose in children through an understanding of pharmacokinetics. DESIGN: A systematic review of the literature was undertaken to seek diamorphine pharmacokinetic parameters in neonates, children and adults. Parenteral and enteral diamorphine bioavailability were reviewed with respect to formation of the major metabolite, morphine. Clinical data quantifying equianalgesic effects of diamorphine and morphine were reviewed. REVIEW SOURCES: PubMed (1960-2020); EMBASE (1980-2020); IPA (1973-2020) and original human research studies that reported diacetylmorphine and metabolite after any dose or route of administration. RESULTS: The systematic review identified 19 studies: 16 in adults and 1 in children and 2 neonatal reports. Details of study participants were extracted. Age ranged from premature neonates to 67 years and weight 1.4-88 kg. Intranasal diamorphine bioavailability was predicted as 50%. The equianalgesic intravenous conversion ratio of morphine:diamorphine was 2:1. There was heterogeneity between pharmacokinetic parameter estimates attributed to routes of administration, lack of size standardisation, methodology and pharmacokinetic analysis. Estimates of the pharmacokinetic parameters clearance and volume of distribution were reduced in neonates. There were insufficient paediatric data to characterise clearance or volume maturation of either diamorphine or its metabolites. CONCLUSIONS: We estimate equianalgesic ratios of intravenous morphine:diamorphine 2:1, intravenous morphine:intranasal diamorphine 1:1 and oral morphine:intranasal diamorphine of 1:3. These ratios are based on adult literature, but are reasonable for deciding on an initial dose of 0.1 mg/kg in children 4-13 years

Nuclear-Targeted Deleted in Liver Cancer 1 (DLC1) Is Less Efficient in Exerting Its Tumor Suppressive Activity Both In Vitro and In Vivo

BACKGROUND: Deleted in liver cancer 1 (DLC1) serves as an important RhoGTPase activating protein (RhoGAP) protein that terminates active RhoA signaling in human cancers. Increasing evidence has demonstrated that the tumor suppressive activity of DLC1 depends not only on RhoGAP activity, but also relies on proper focal adhesion localization through its interaction with tensin family proteins. Recently, there are reports showing that DLC1 can also be found in the nucleus; however, the existence and the relative tumor suppressive activity of nuclear DLC1 have never been clearly addressed. METHODOLOGY AND PRINCIPAL FINDINGS: We herein provide new evidence that DLC1 protein, which predominantly associated with focal adhesions and localized in cytosol, dynamically shuttled between cytoplasm and nucleus. Treatment of cells with nuclear export blocker, Leptomycin B (LMB), retained DLC1 in the nucleus. To understand the nuclear entry of DLC1, we identified amino acids 600-700 of DLC1 as a novel region that is important for its nuclear localization. The tumor suppressive activity of nuclear DLC1 was directly assessed by employing a nuclear localization signal (NLS) fusion variant of DLC1 (NLS-DLC1) with preferential nuclear localization. In SMMC-7721 HCC cells, expression of NLS-DLC1 failed to suppress colony formation and actin stress fiber formation in vitro. The abrogated tumor suppressive activity of nuclear DLC1 was demonstrated for the first time in vivo by subcutaneously injecting p53(-/-) RasV12 hepatoblasts with stable NLS-DLC1 expression in nude mice. The injected hepatoblasts with NLS-DLC1 expression effectively formed tumors when compared with the non-nuclear targeted DLC1. CONCLUSIONS/SIGNIFICANCE: Our study identified a novel region responsible for the nuclear entry of DLC1 and demonstrated the functional difference of DLC1 in different cellular compartments both in vitro and in vivo

An investigation of the smoking behaviours of parents before, during and after the birth of their children in Taiwan

[[abstract]]Background: Although many studies have investigated the negative effects of parental smoking on children and Taiwan has started campaigns to promote smoke-free homes, little is known about the smoking behaviours of Taiwanese parents during the childbearing period. To help fill the gap, this study investigated Taiwanese parents' smoking behaviours before, during and after the birth of their children, particularly focusing on smoking cessation during pregnancy and relapse after childbirth. Methods: We used data from the Survey of Health Status of Women and Children, conducted by Taiwan's National Health Research Institutes in 2000. After excluding survey respondents with missing information about their smoking behaviours, our sample consisted of 3,109 women who were married at the time of interview and had at least one childbearing experience between March 1, 1995 and February 28, 1999. Data on parental smoking behaviour in the six months before pregnancy, during pregnancy, and in the first year after childbirth were extracted from the survey and analysed by descriptive statistics as well as logistic regression. Results: Four percent of the mothers and sixty percent of the fathers smoked before the conception of their first child. The educational attainment and occupation of the parents were associated with their smoking status before the first pregnancy in the family. Over 80% of smoking mothers did not quit during pregnancy, and almost all of the smoking fathers continued tobacco use while their partners were pregnant. Over two thirds of the women who stopped smoking during their pregnancies relapsed soon after childbirth. Very few smoking men stopped tobacco use while their partners were pregnant, and over a half of those who quit started to smoke again soon after their children were born. Conclusion: Among Taiwanese women who had childbearing experiences in the late 1990s, few smoked. Of those who smoked, few quit during pregnancy. Most of those who quit relapsed in the first year after childbirth. The smoking prevalence was high among the husbands of these Taiwanese women, and almost all of these smoking fathers continued tobacco use while their partners were pregnant. It is important to advocate the benefits of a smoke-free home to Taiwanese parents-to-be and parents with young children, especially the fathers. The government should take advantage of its free prenatal care and well-child care services to do this. In addition to educational campaigns through the media, the government can request physicians to promote smoke-free homes when they deliver prenatal care and well-child care. This could help reduce young children's health risks from their mothers' smoking during pregnancy and second-hand smoke at home

HOXB5 Cooperates with NKX2-1 in the Transcription of Human RET

The enteric nervous system (ENS) regulates peristaltic movement of the gut, and abnormal ENS causes Hirschsprung's disease (HSCR) in newborns. HSCR is a congenital complex genetic disorder characterised by a lack of enteric ganglia along a variable length of the intestine. The receptor tyrosine kinase gene (RET) is the major HSCR gene and its expression is crucial for ENS development. We have previously reported that (i) HOXB5 transcription factor mediates RET expression, and (ii) mouse with defective HOXB5 activity develop HSCR phenotype. In this study, we (i) elucidate the underlying mechanisms that HOXB5 mediate RET expression, and (ii) examine the interactions between HOXB5 and other transcription factors implicated in RET expression. We show that human HOXB5 binds to the promoter region 5′ upstream of the binding site of NKX2-1 and regulates RET expression. HOXB5 and NKX2-1 form a protein complex and mediate RET expression in a synergistic manner. HSCR associated SNPs at the NKX2-1 binding site (-5G>A rs10900296; -1A>C rs10900297), which reduce NKX2-1 binding, abolish the synergistic trans-activation of RET by HOXB5 and NKX2-1. In contrast to the synergistic activation of RET with NKX2-1, HOXB5 cooperates in an additive manner with SOX10, PAX3 and PHOX2B in trans-activation of RET promoter. Taken together, our data suggests that HOXB5 in coordination with other transcription factors mediates RET expression. Therefore, defects in cis- or trans-regulation of RET by HOXB5 could lead to reduction of RET expression and contribute to the manifestation of the HSCR phenotype

Ubiquitin Ligase RNF146 Regulates Tankyrase and Axin to Promote Wnt Signaling

Canonical Wnt signaling is controlled intracellularly by the level of β-catenin protein, which is dependent on Axin scaffolding of a complex that phosphorylates β-catenin to target it for ubiquitylation and proteasomal degradation. This function of Axin is counteracted through relocalization of Axin protein to the Wnt receptor complex to allow for ligand-activated Wnt signaling. AXIN1 and AXIN2 protein levels are regulated by tankyrase-mediated poly(ADP-ribosyl)ation (PARsylation), which destabilizes Axin and promotes signaling. Mechanistically, how tankyrase limits Axin protein accumulation, and how tankyrase levels and activity are regulated for this function, are currently under investigation. By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. RNF146 also destabilizes tankyrases TNKS1 and TNKS2 proteins and, in a reciprocal relationship, tankyrase activity reduces RNF146 protein levels. We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation. RNF146 is a cytoplasmic protein that also prevents tankyrase protein aggregation at a centrosomal location. Tankyrase auto-PARsylation and PARsylation of Axin is known to lead to proteasome-mediated degradation of these proteins, and we demonstrate that, through ubiquitylation, RNF146 mediates this process to regulate Wnt signaling

Evolutionary and Transmission Dynamics of Reassortant H5N1 Influenza Virus in Indonesia

H5N1 highly pathogenic avian influenza (HPAI) viruses have seriously affected the Asian poultry industry since their recurrence in 2003. The viruses pose a threat of emergence of a global pandemic influenza through point mutation or reassortment leading to a strain that can effectively transmit among humans. In this study, we present phylogenetic evidences for the interlineage reassortment among H5N1 HPAI viruses isolated from humans, cats, and birds in Indonesia, and identify the potential genetic parents of the reassorted genome segments. Parsimony analyses of viral phylogeography suggest that the reassortant viruses may have originated from greater Jakarta and surroundings, and subsequently spread to other regions in the West Java province. In addition, Bayesian methods were used to elucidate the genetic diversity dynamics of the reassortant strain and one of its genetic parents, which revealed a more rapid initial growth of genetic diversity in the reassortant viruses relative to their genetic parent. These results demonstrate that interlineage exchange of genetic information may play a pivotal role in determining viral genetic diversity in a focal population. Moreover, our study also revealed significantly stronger diversifying selection on the M1 and PB2 genes in the lineages preceding and subsequent to the emergence of the reassortant viruses, respectively. We discuss how the corresponding mutations might drive the adaptation and onward transmission of the newly formed reassortant viruses

5-Fluorouracil Induced Intestinal Mucositis via Nuclear Factor-κB Activation by Transcriptomic Analysis and In Vivo Bioluminescence Imaging

5-Fluorouracil (5-FU) is a commonly used drug for the treatment of malignant cancers. However, approximately 80% of patients undergoing 5-FU treatment suffer from gastrointestinal mucositis. The aim of this report was to identify the drug target for the 5-FU-induced intestinal mucositis. 5-FU-induced intestinal mucositis was established by intraperitoneally administering mice with 100 mg/kg 5-FU. Network analysis of gene expression profile and bioluminescent imaging were applied to identify the critical molecule associated with 5-FU-induced mucositis. Our data showed that 5-FU induced inflammation in the small intestine, characterized by the increased intestinal wall thickness and crypt length, the decreased villus height, and the increased myeloperoxidase activity in tissues and proinflammatory cytokine production in sera. Network analysis of 5-FU-affected genes by transcriptomic tool showed that the expression of genes was regulated by nuclear factor-κB (NF-κB), and NF-κB was the central molecule in the 5-FU-regulated biological network. NF-κB activity was activated by 5-FU in the intestine, which was judged by in vivo bioluminescence imaging and immunohistochemical staining. However, 5-aminosalicylic acid (5-ASA) inhibited 5-FU-induced NF-κB activation and proinflammatory cytokine production. Moreover, 5-FU-induced histological changes were improved by 5-ASA. In conclusion, our findings suggested that NF-κB was the critical molecule associated with the pathogenesis of 5-FU-induced mucositis, and inhibition of NF-κB activity ameliorated the mucosal damage caused by 5-FU