The Case for Perspicuous Programming

This essay examines the nature of programs, classifies the traditional or enigmatic styles of programming, distinguishing template, prose and literate styles; notes the contrast between batch programs and interactive programs; and highlights the advantages of giving priority in developing interactive programs to the online documentation, and proposes that this documentation should be the principal target of development, with the executable program code being regarded of secondary and consequent

Quantum non-demolition (QND) modulation of quantum interference

We propose an experiment where quantum interference between two different paths is modulated by means of a QND measurement on one or both the arm of the interferometer. The QND measurement is achieved in a Kerr cell. We illustrate a scheme for the realisation of this experiment and some further developments.Comment: accepted for publicatio

The Time-Energy Uncertainty Relation

The time energy uncertainty relation has been a controversial issue since the advent of quantum theory, with respect to appropriate formalisation, validity and possible meanings. A comprehensive account of the development of this subject up to the 1980s is provided by a combination of the reviews of Jammer (1974), Bauer and Mello (1978), and Busch (1990). More recent reviews are concerned with different specific aspects of the subject. The purpose of this chapter is to show that different types of time energy uncertainty relation can indeed be deduced in specific contexts, but that there is no unique universal relation that could stand on equal footing with the position-momentum uncertainty relation. To this end, we will survey the various formulations of a time energy uncertainty relation, with a brief assessment of their validity, and along the way we will indicate some new developments that emerged since the 1990s.Comment: 33 pages, Latex. This expanded version (prepared for the 2nd edition of "Time in quantum mechanics") contains minor corrections, new examples and pointers to some additional relevant literatur

Von Bezold assimilation effect reverses in stereoscopic conditions

Lightness contrast and lightness assimilation are opposite phenomena: in contrast, grey targets appear darker when bordering bright surfaces (inducers) rather than dark ones; in assimilation, the opposite occurs. The question is: which visual process favours the occurrence of one phenomenon over the other? Researchers provided three answers to this question. The first asserts that both phenomena are caused by peripheral processes; the second attributes their occurrence to central processes; and the third claims that contrast involves central processes, whilst assimilation involves peripheral ones. To test these hypotheses, an experiment on an IT system equipped with goggles for stereo vision was run. Observers were asked to evaluate the lightness of a grey target, and two variables were systematically manipulated: (i) the apparent distance of the inducers; and (ii) brightness of the inducers. The retinal stimulation was kept constant throughout, so that the peripheral processes remained the same. The results show that the lightness of the target depends on both variables. As the retinal stimulation was kept constant, we conclude that central mechanisms are involved in both lightness contrast and lightness assimilation

Influence of common polymorphisms in the SLC5A2 gene on metabolic traits in subjects at increased risk of diabetes and on response to empagliflozin treatment in patients with diabetes.

Objective Inhibition of the renal sodium-glucose cotransporter 2 (SGLT2) is a novel concept in the therapy of diabetes mellitus. In this study, we first assessed whether common single nucleotide polymorphisms (SNPs) in the SGLT2-encoding gene SLC5A2 affect diabetes-related metabolic traits in subjects at risk for type 2 diabetes and, second, whether these have pharmacogenetic relevance by interfering with the response to empagliflozin treatment in patients with type 2 diabetes. Patients and methods Samples from a metabolically well-phenotyped cross-sectional study population (total N=2600) at increased risk for type 2 diabetes and pooled pharmacogenetic samples from patients from four phase III trials of empagliflozin (in total: 603 receiving empagliflozin, 305 receiving placebo) were genotyped for five common SNPs (minor allele frequencies >= 5%) present in the SLC5A2 gene locus. Results In the cross-sectional study, none of the SLC5A2 SNPs significantly influenced metabolic traits such as body fat, insulin sensitivity/resistance, insulin release, HbA(1c), plasma glucose, or systolic blood pressure when multiple testing was taken into account (all P >= 0.0083). Further, no relevant effect on response to treatment with empagliflozin on HbA(1c), fasting glucose, weight, or systolic blood pressure was observed for the SNPs tested in the pharmacogenetic study. Conclusion Common genetic variants in the SLC5A2 gene neither affects diabetes-related metabolic traits nor have a clinically relevant impact on response to treatment with the SGLT2 inhibitor empagliflozin

Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype.

Reducing expression of the fetal hemoglobin (HbF) repressor BCL11A leads to a simultaneous increase in γ-globin expression and reduction in β-globin expression. Thus, there is interest in targeting BCL11A as a treatment for β-hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia. Here, we found that using optimized shRNAs embedded within an miRNA (shRNAmiR) architecture to achieve ubiquitous knockdown of BCL11A profoundly impaired long-term engraftment of both human and mouse hematopoietic stem cells (HSCs) despite a reduction in nonspecific cellular toxicities. BCL11A knockdown was associated with a substantial increase in S/G2-phase human HSCs after engraftment into immunodeficient (NSG) mice, a phenotype that is associated with HSC exhaustion. Lineage-specific, shRNAmiR-mediated suppression of BCL11A in erythroid cells led to stable long-term engraftment of gene-modified cells. Transduced primary normal or SCD human HSCs expressing the lineage-specific BCL11A shRNAmiR gave rise to erythroid cells with up to 90% reduction of BCL11A protein. These erythrocytes demonstrated 60%-70% γ-chain expression (vs. < 10% for negative control) and a corresponding increase in HbF. Transplantation of gene-modified murine HSCs from Berkeley sickle cell mice led to a substantial improvement of sickle-associated hemolytic anemia and reticulocytosis, key pathophysiological biomarkers of SCD. These data form the basis for a clinical trial application for treating sickle cell disease

Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas

Objectives/Hypothesis: Recent studies indicate that vestibular schwannomas (VSs) rely on phosphatidylinositol 3-kinase/AKT activation to promote cell proliferation and survival; therefore, targeting AKT may provide new therapeutic options. We have previously shown that AR42, a novel histone deacetylase inhibitor, potently suppresses VS growth in vitro at doses correlating with AKT inactivation. The objectives of the current study were translational: 1) to examine the end biologic effects of AR42 on tumor growth in vivo, 2) to validate AKT as its in vivo molecular target, 3) to determine whether AR42 penetrates the blood-brain barrier (BBB), and 4) to study the pharmacotoxicity profile of AR42. Study Design: In vivo mouse studies. Methods: AR42 was dosed orally in murine schwannoma allografts and human VS xenografts. Magnetic resonance imaging was used to quantify changes in tumor volume, and intracellular molecular targets were analyzed using immunohistochemistry. BBB penetration was assayed, and both blood-chemistry measurements and histology studies were used to evaluate toxicity. Results: Growth of schwannoma implants was dramatically decreased by AR42 at doses correlating with AKT dephosphorylation, cell cycle arrest, and apoptosis. AR42 penetrated the BBB, and wild-type mice fed AR42 for 6 months behaved normally and gained weight appropriately. Blood-chemistry studies and organ histology performed after 3 and 6 months of AR42 treatment demonstrated no clinically significant abnormalities. Conclusions: AR42 suppresses schwannoma growth at doses correlating with AKT pathway inhibition. This orally bioavailable drug penetrates the BBB, is well tolerated, and represents a novel candidate for translation to human VS clinical trials. © 2011 The American Laryngological, Rhinological, and Otological Society, Inc