Abstract Datatypes for Real Numbers in Type Theory

Abstract. We propose an abstract datatype for a closed interval of real numbers to type theory, providing a representation-independent approach to programming with real numbers. The abstract datatype requires only function types and a natural numbers type for its formulation, and so can be added to any type theory that extends Gödel’s System datatype is equivalent in power to programming intensionally with representations of real numbers. We also consider representing arbitrary real numbers using a mantissa-exponent representation in which the mantissa is taken from the abstract interval.

A coinductive semantics of the Unlimited Register Machine

We exploit (co)inductive specifications and proofs to approach the evaluation of low-level programs for the Unlimited Register Machine (URM) within the Coq system, a proof assistant based on the Calculus of (Co)Inductive Constructions type theory. Our formalization allows us to certify the implementation of partial functions, thus it can be regarded as a first step towards the development of a workbench for the formal analysis and verification of both converging and diverging computations

Propylthiouracil Is Teratogenic in Murine Embryos

Background: Hyperthyroidism during pregnancy is treated with the antithyroid drugs (ATD) propylthiouracil (PTU) and methimazole (MMI). PTU currently is recommended as the drug of choice during early pregnancy. Yet, despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have not been performed. Methods: We examined the teratogenic effects of PTU and MMI during embryogenesis in mice. To span different periods of embryogenesis, dams were treated with compounds or vehicle daily from embryonic day (E) 7.5 to 9.5 or from E3.5 to E7.5. Embryos were examined for gross malformations at E10.5 or E18.5 followed by histological and micro-CT analysis. Influences of PTU on gene expression levels were examined by RNA microarray analysis. Results: When dams were treated from E7.5 to E9.5 with PTU, neural tube and cardiac abnormalities were observed at E10.5. Cranial neural tube defects were significantly more common among the PTU-exposed embryos than those exposed to MMI or vehicle. Blood in the pericardial sac, which is a feature indicative of abnormal cardiac function and/or abnormal vasculature, was observed more frequently in PTU-treated than MMI-treated or vehicle-treated embryos. Following PTU treatment, a total of 134 differentially expressed genes were identified. Disrupted genetic pathways were those associated with cytoskeleton remodeling and keratin filaments. At E 18.5, no gross malformations were evident in either ATD group, but the number of viable PTU embryos per dam at E18.5 was significantly lower from those at E10.5, indicating loss o

Applications and Techniques for Fast Machine Learning in Science

In this community review report, we discuss applications and techniques for fast machine learning (ML) in science - the concept of integrating powerful ML methods into the real-time experimental data processing loop to accelerate scientific discovery. The material for the report builds on two workshops held by the Fast ML for Science community and covers three main areas: applications for fast ML across a number of scientific domains; techniques for training and implementing performant and resource-efficient ML algorithms; and computing architectures, platforms, and technologies for deploying these algorithms. We also present overlapping challenges across the multiple scientific domains where common solutions can be found. This community report is intended to give plenty of examples and inspiration for scientific discovery through integrated and accelerated ML solutions. This is followed by a high-level overview and organization of technical advances, including an abundance of pointers to source material, which can enable these breakthroughs

Genetic susceptibility to infectious diseases

The clinical outcome of infectious disease (ID) is determined by a complex interaction between microorganism, host genetic factors and environment. Epidemiological studies have revealed differences within and between populations exposed to the same infectious agent, and in the prevalence or severity of the disease, underlying the relevance of the genetic background. Population genetic studies have estimated the genetic component (susceptibility) in the ID determination and have identified some susceptibility gene(s)/polymorphism(s). This paper describes the methods used in genetic epidemiology. Complex segregation analysis is used to define genetic models. Parametric linkage analysis and association studies are used to identify polymorphisms strongly linked to the disease. Genome-wide scan and microarray technology are used to map and identify major genes for ID. Future developments will identify subgroups of subjects at different risks of developing ID

Teratology information services in europe and their contribution to the prevention of congenital anomalies

OBJECTIVES: To inform on Teratology Information Services (TIS) in Europe, their history, function and activity in preventing congenital malformations. CONCLUSIONS: Clinical teratology tries to identify human teratogens. TIS play an important role in public health by providing counsel on known reproductive risks and conducting specific research. This has led to a reduction in unnecessary fears of pregnant women and pregnancy terminations, as well as to better, more appropriate drug selection to treat acute or chronic disease. In addition, TIS units also conduct prospective studies and inform the public and physicians of the possible effects of environmental agents on the developing embryo and fetus

Are congenital anorectal malformations more frequent in newborns conceived with assisted reproductive techniques?

One of the major concerns about ART is the risk of birth defects in children born after in vitro fertilization. We report on a cohort of consecutive children affected with anorectal malformation (ARM) requiring surgical correction in which we found a significantly high proportion (Odds ratio 13.31, 95% confidence limits 4.0-39.6) of children born after ART. Our data is in agreement with the result of a recent epidemiological study in Sweden. Further studies are necessary to define the risk and identify the causes, if any. At present, couples undergoing ART should be informed of the general risk of congenital anomalies, of which, ARM can be suggested as an example

Genetic susceptibility to teratogens: State of the art.

There is evidence that the susceptibility to the teratogenic effect of drugs within human populations varies extremely from one individual to another, even after identical exposures. One of the factors that may explain these interindividual differences is the genetic makeup in the pharmacokinetics and pharmacodynamics of the respective drugs. In fact, both maternal and embryonic/fetal genotypes can affect placental transport, absorption, metabolism, distribution and receptor binding of an agent, influencing its teratogenicity. We have reviewed the literature and commented on the reported correlations between genetic factors and drug-induced birth defects. There is still a clear lack of knowledge regarding this issue and the available data are often conflicting. However, the identification of specific polymorphisms associated with predisposition to teratogenesis may allow in the future the development of personalized non-teratogenic therapies for pregnant women

METHIMAZOLE EMBRYOPATHY. DELINEATION OF THE PHENOTYPE

We report on a further case of congenital anomalies in a child exposed to methimazole during the first trimester of pregnancy (from first to seventh gestational week), and define a specific malformation pattern related to prenatal methimazole exposure and consisting of choanal and esophageal atresia, scalp defects, minor facial anomalies and psychomotor delay

Substitution of a pentalenolactone-sensitive glyceraldehyde-3-phosphate dehydrogenase by a genetically distinct resistant isoform accompanies pentalenolactone production in Streptomyces arenae.

Pentalenolactone (PL), an antibiotic produced by Streptomyces arenae, is a potent inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The producer strain contains different isoforms of GAPDH: a PL-sensitive enzyme on nonproduction media and a PL-insensitive enzyme on production media. After induction of PL synthesis, the sensitive GAPDH disappears parallel to the disappearance of its activity, as shown by Western (immunoblot) hybridization. The two isoenzymes exhibit little immunological cross-reactivity and differ in size, amino acid composition, and several amino acid residues of their amino termini. Two different types of plasmids from a S. arenae genomic library, named pBRPLR1 and pBRPLR2, were cloned in Escherichia coli by selection for enhanced PL resistance. Both contain a GAPDH structural gene. Plasmid pBRPLR1 increases E. coli PL tolerance 7-fold, and plasmid pBRPLR2 increases it 30-fold. GAPDH from pBRPLR1 transformants shows biphasic PL inactivation kinetics. These cells contain PL-sensitive GAPDH from both E. coli and S. arenae. GAPDH from pBRPLR2 transformants tolerates higher PL concentrations than either E. coli or S. arenae PL-sensitive GAPDH but is less resistant than S. arenae PL-insensitive GAPDH. Nondenaturing polyacrylamide electrophoresis showed this GAPDH to be a hybrid of E. coli and S. arenae PL-insensitive GAPDH. The hybrid enzyme could be purified to homogeneity. Induction of the lacZ promoter of pUC subclones of both GAPDH genes had only a small effect on raising the level of intracellular GAPDH