A developmental evaluation approach to lesson study: exploring the impact of lesson study in London schools

This article presents a methodology for the developmental evaluation of a lesson study programme in primary and secondary schools. Our approach combined the principles of (i) user-focused evaluation, in which, as evaluators, we acted as participatory members of the innovation team and sought to involve users in the design and implementation of evaluation tools, (ii) a multi-level logical model to guide data collection and impact measurement and (iii) an ‘improving rather than proving’ approach to evaluation. The evaluation tools were used on a programme to promote lesson study in London schools involving 133 teachers and 33 schools. The evaluation methodology included outcomes at school leadership, teacher and student levels. Issues of internal and external validity are discussed and strengths and weaknesses are described. Findings showed promise in the use of our scale to measure changes in teacher pedagogical outcomes and in the recording of qualitative changes to both teachers and students as a result of the lesson study cycles. Suggestions for the future use and development of this methodology are proposed, including better use of control groups and quantitative measures to record changes in learning outcomes for students. List of Abbreviations: HE: Higher Education; LS: Lesson Study; PD: Professional Developmen

Cystic Fibrosis: A New Target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines

The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity

Proteostasis Regulators in Cystic Fibrosis: Current Development and Future Perspectives

In cystic fibrosis (CF), the deletion of phenylalanine 508 (F508del) in the CF transmembrane conductance regulator (CFTR) leads to misfolding and premature degradation of the mutant protein. These defects can be targeted with pharmacological agents named potentiators and correctors. During the past years, several efforts have been devoted to develop and approve new effective molecules. However, their clinical use remains limited, as they fail to fully restore F508del-CFTR biological function. Indeed, the search for CFTR correctors with different and additive mechanisms has recently increased. Among them, drugs that modulate the CFTR proteostasis environment are particularly attractive to enhance therapy effectiveness further. This Perspective focuses on reviewing the recent progress in discovering CFTR proteostasis regulators, mainly describing the design, chemical structure, and structure-activity relationships. The opportunities, challenges, and future directions in this emerging and promising field of research are discussed, as well

A learning-based shared control architecture for interactive task execution

Shared control is a key technology for various robotic applications in which a robotic system and a human operator are meant to collaborate efficiently. In order to achieve efficient task execution in shared control, it is essential to predict the desired behavior for a given situation or context to simplify the control task for the human operator. To do this prediction, we use Learning from Demonstration (LfD), which is a popular approach for transferring human skills to robots. We encode the demonstrated behavior as trajectory distributions and generalize the learned distributions to new situations. The goal of this paper is to present a shared control framework that uses learned expert distributions to gain more autonomy. Our approach controls the balance between the controller’s autonomy and the human preference based on the distributions of the demonstrated trajectories. Moreover, the learned distributions are autonomously refined from collaborative task executions, resulting in a master-slave system with increasing autonomy that requires less user input with an increasing number of task executions. We experimentally validated that our shared control approach enables efficient task executions. Moreover, the conducted experiments demonstrated that the developed system improves its performances through interactive task executions with our shared control

Анализ распространения трещин гидравлического разрыва пласта (ГРП) после проведения повторного многостадийного ГРП на горизонтальных скважинах на примере нефтяного месторождения Нюрольской впадины

Объектом исследования является пласт Ю11 верхневасюганской подсвиты месторождения N, в который пробурены вертикальные и горизонтальные скважины, в которых был произведен гидравлический разрыв пласта. Целью работы является определение направления распространения трещин повторного гидравлического разрыва пласта (ГРП) в зависимости от времени работы скважины и дальнейший дизайн оптимальной операции. В процессе работы произведен анализ существующей литературы по исследуемой теме, выявлены не разрешенные вопросы на настоящий момент. Методика расчета изменения поля напряжений в результате отбора флюда была предложена и обоснована. Произведено моделирование поля напряжений для различных типов скважин, а также гидродинамическое моделирование.The objects of the study is U11 horizon of Verhne-Vasyoganian formation, which is penetrated by vertical and horizontal wells which were hydraulically fractured. The aim of the study is to determine the direction of fracture propagation which was induced during refracturing treatment depending on well flowing time and to design following optimal treatment. The analysis of exist literature about the theme was made and the exist problems were determined during the study. The method of stress field changing estimation due to the was proposed and approved. Stress field modelling around various types of wells and following simulation study in order to select the most effective treatment were performed

Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors

RNF5, an endoplasmic reticulum (ER) E3 ubiquitin ligase, participates to the ER-associated protein degradation guaranteeing the protein homeostasis. Depending on tumor model tested, RNF5 exerts pro-or anti-tumor activity. The aim of this study was to elucidate the controversial role of RNF5 in neuroblastoma and melanoma, two neuroectodermal tumors of infancy and adulthood, respectively. RNF5 gene levels are evaluated in publicly available datasets reporting the gene expression profile of melanoma and neuroblastoma primary tumors at diagnosis. The therapeutic effect of Analog-1, an RNF5 pharmacological activator, was investigated on in vitro and in vivo neuroblastoma and melanoma models. In both neuroblastoma and melanoma patients the high expression of RNF5 correlated with a better prognostic outcome. Treatment of neuroblastoma and melanoma cell lines with Analog-1 reduced cell viability by impairing the glutamine availability and energy metabolism through inhibition of F1Fo ATP-synthase activity. This latter event led to a marked increase in oxidative stress, which, in turn, caused cell death. Similarly, neuroblastoma-and melanoma-bearing mice treated with Analog-1 showed a significant delay of tumor growth in comparison to those treated with vehicle only. These findings validate RNF5 as an innovative drug target and support the development of Analog-1 in early phase clinical trials for neuroblastoma and melanoma patients

Virtual Drug Repositioning as a Tool to Identify Natural Small Molecules That Synergize with Lumacaftor in F508del-CFTR Binding and Rescuing

Cystic fibrosis is a hereditary disease mainly caused by the deletion of the Phe 508 (F508del) of the cystic fibrosis transmembrane conductance regulator (CFTR) protein that is thus withheld in the endoplasmic reticulum and rapidly degraded by the ubiquitin/proteasome system. Cystic fibrosis remains a potentially fatal disease, but it has become treatable as a chronic condition due to some CFTR-rescuing drugs that, when used in combination, increase in their therapeutic effect due to a synergic action. Also, dietary supplementation of natural compounds in combination with approved drugs could represent a promising strategy to further alleviate cystic fibrosis symptoms. On these bases, we screened by in silico drug repositioning 846 small synthetic or natural compounds from the AIFA database to evaluate their capacity to interact with the highly druggable lumacaftor binding site of F508del-CFTR. Among the identified hits, nicotinamide (NAM) was predicted to accommodate into the lumacaftor binding region of F508del-CFTR without competing against the drug but rather stabilizing its binding. The effective capacity of NAM to bind F508del-CFTR in a lumacaftor-uncompetitive manner was then validated experimentally by surface plasmon resonance analysis. Finally, the capacity of NAM to synergize with lumacaftor increasing its CFTR-rescuing activity was demonstrated in cell-based assays. This study suggests the possible identification of natural small molecules devoid of side effects and endowed with the capacity to synergize with drugs currently employed for the treatment of cystic fibrosis, which hopefully will increase the therapeutic efficacy with lower doses

Normal calcium-activated anion secretion in a mouse selectively lacking TMEM16A in intestinal epithelium

Calcium-activated anion secretion is expected to ameliorate cystic fibrosis, a genetic disease that carries an anion secretory defect in exocrine tissues. Human patients and animal models of the disease that present a mild intestinal phenotype have been postulated to bear a compensatory calcium-activated anion secretion in the intestine. TMEM16A is calcium-activated anion channel whose presence in the intestinal epithelium is contradictory. We aim to test the functional expression of TMEM16A using animal models with Cftr and/or Tmem16a intestinal silencing. Expression of TMEM16A was studied in a wild type and intestinal Tmem16a knockout mice by mRNA-seq, mass-spectrometry, q-PCR, Western blotting and immunolocalization. Calcium-activated anion secretion was recorded in the ileum and proximal colon of these animals including intestinal Cftr knockout and double mutants with dual Tmem16a and Cftr intestinal ablation. Mucus homeostasis was studied by immune-analysis of Mucin-2 (Muc2) and survival curves were recorded. Tmem16a transcript was found in intestine. Nevertheless, protein was barely detected in colon samples. Electrophysiological measurements demonstrated that the intestinal deletion of Tmem16a did not change calcium-activated anion secretion induced by carbachol or ATP in ileum and proximal colon. Muc2 architecture was not altered by Tmem16a silencing as was observed when Cftr was deleted from mouse intestine. Tmem16a silencing neither affected animal survival nor modified the lethality observed in the intestinal Cftr-null mouse. Our results demonstrate that TMEM16A function in the murine intestine is not related to electrogenic calcium-activated anion transport and does not affect mucus homeostasis and survival of animals