Intestinal microbiota in human health and disease: the impact of probiotics

The complex communities of microorganisms that colonise the human gastrointestinal tract play an important role in human health. The development of culture-independent molecular techniques has provided new insights in the composition and diversity of the intestinal microbiota. Here, we summarise the present state of the art on the intestinal microbiota with specific attention for the application of high-throughput functional microbiomic approaches to determine the contribution of the intestinal microbiota to human health. Moreover, we review the association between dysbiosis of the microbiota and both intestinal and extra-intestinal diseases. Finally, we discuss the potential of probiotic microorganism to modulate the intestinal microbiota and thereby contribute to health and well-being. The effects of probiotic consumption on the intestinal microbiota are addressed, as well as the development of tailor-made probiotics designed for specific aberrations that are associated with microbial dysbiosis

Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms

Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption1. Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers1,2. Cells are protected against acetaldehyde-induced damage by DNA crosslink repair, which when impaired causes Fanconi anaemia (FA), a disease resulting in failure to produce blood cells and a predisposition to cancer3,4. The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells5,6,7. However, the nature of the DNA damage induced by acetaldehyde and how this is repaired remains a key question. Here we generate acetaldehyde-induced DNA interstrand crosslinks and determine their repair mechanism in Xenopus egg extracts. We find that two replication-coupled pathways repair these lesions. The first is the FA pathway, which operates using excision—analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin. However, the repair of acetaldehyde-induced crosslinks results in increased mutation frequency and an altered mutational spectrum compared with the repair of cisplatin-induced crosslinks. The second repair mechanism requires replication fork convergence, but does not involve DNA incisions—instead the acetaldehyde crosslink itself is broken. The Y-family DNA polymerase REV1 completes repair of the crosslink, culminating in a distinct mutational spectrum. These results define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism

Ribosome profiling reveals the what, when, where and how of protein synthesis

Ribosome profiling, which involves the deep sequencing of ribosome-protected mRNA fragments, is a powerful tool for globally monitoring translation in vivo. The method has facilitated discovery of the regulation of gene expression underlying diverse and complex biological processes, of important aspects of the mechanism of protein synthesis, and even of new proteins, by providing a systematic approach for experimental annotation of coding regions. Here, we introduce the methodology of ribosome profiling and discuss examples in which this approach has been a key factor in guiding biological discovery, including its prominent role in identifying thousands of novel translated short open reading frames and alternative translation products

AN EXPERIMENTAL-STUDY TO EVALUATE THE EFFECTIVENESS OF DIFFERENT METHODS AND INTENSITIES OF LAW-ENFORCEMENT ON DRIVING SPEED ON MOTORWAYS

Two field experiments were conducted to establish the most effective method of enforcement in reducing driving speed and to establish the most efficient strategy in terms of police force personnel required. In the first experiment, the effect of three variables on driving speed on motorways was studied. The first variable, intensity of enforcement, was manipulated by creating three different objective levels of apprehension for detected speeding drivers. The second variable was method of enforcement. On-view stopping and ticketing of offenders was compared to mailing of fines on the basis of the car's licence plate number. The third variable manipulated was the time delay in the mailing of fines. Time delay between detection of the offence and feedback to the driver was shortened in one condition. In a second experiment, police enforcement effort was optimized by relating intensity level of enforcement to the proportion of speeding vehicles. In the first experiment, police enforcement was applied for four weeks; in the second experiment, enforcement activities were continued for 12 consecutive weeks. In both cases the main dependent variable was driving speed. Before, during, and after the application of enforcement, speed was registered using induction loops. In addition, driver opinion about speeding and speed enforcement was studied using postal questionnaire surveys. The results show the largest and longest lasting reduction in driving speed in the highest intensity level-condition, giving support for a relation between objective chance of apprehension and speed choice. On-view stopping of offenders was shown to be a more effective method to reduce driving speed than mailing of fines. Some of these results are discussed in the light of game theory. The questionnaire surveys indicated that most drivers did not notice the recurrence in enforcement activities due to infrequent passing of the sections of motorways studied. The preventive effect of police enforcement appeared to be far more substantial than its repressive effect. Enforcement primarily deters the current nonoffender from speeding