Divergent expression of claudin -1, -3, -4, -5 and -7 in developing human lung

<p>Abstract</p> <p>Background</p> <p>Claudins are the main components of tight junctions, structures which are associated with cell polarity and permeability. The aim of this study was to analyze the expression of claudins 1, 3, 4, 5, and 7 in developing human lung tissues from 12 to 40 weeks of gestation.</p> <p>Methods</p> <p>47 cases were analyzed by immunohistochemisty for claudins 1, 3, 4, 5 and 7. 23 cases were also investigated by quantitative RT-PCR for claudin-1, -3 and -4.</p> <p>Results</p> <p>Claudin-1 was expressed in epithelium of bronchi and large bronchioles from week 12 onwards but it was not detected in epithelium of developing alveoli. Claudin-3, -4 and -7 were strongly expressed in bronchial epithelium from week 12 to week 40, and they were also expressed in alveoli from week 16 to week 40. Claudin-5 was expressed strongly during all periods in endothelial cells. It was expressed also in epithelium of bronchi from week 12 to week 40, and in alveoli during the canalicular period. RT-PCR analyses revealed detectable amounts of RNAs for claudins 1, 3 and 4 in all cases studied.</p> <p>Conclusion</p> <p>Claudin-1, -3, -4, -5, and -7 are expressed in developing human lung from week 12 to week 40 with distinct locations and in divergent quantities. The expression of claudin-1 was restricted to the bronchial epithelium, whereas claudin-3, -4 and -7 were positive also in alveolar epithelium as well as in the bronchial epithelium. All claudins studied are linked to the development of airways, whereas claudin-3, -4, -5 and -7, but not claudin-1, are involved in the development of acinus and the differentiation of alveolar epithelial cells.</p

Age-related delay in information accrual for faces: Evidence from a parametric, single-trial EEG approach

Background: In this study, we quantified age-related changes in the time-course of face processing by means of an innovative single-trial ERP approach. Unlike analyses used in previous studies, our approach does not rely on peak measurements and can provide a more sensitive measure of processing delays. Young and old adults (mean ages 22 and 70 years) performed a non-speeded discrimination task between two faces. The phase spectrum of these faces was manipulated parametrically to create pictures that ranged between pure noise (0% phase information) and the undistorted signal (100% phase information), with five intermediate steps. Results: Behavioural 75% correct thresholds were on average lower, and maximum accuracy was higher, in younger than older observers. ERPs from each subject were entered into a single-trial general linear regression model to identify variations in neural activity statistically associated with changes in image structure. The earliest age-related ERP differences occurred in the time window of the N170. Older observers had a significantly stronger N170 in response to noise, but this age difference decreased with increasing phase information. Overall, manipulating image phase information had a greater effect on ERPs from younger observers, which was quantified using a hierarchical modelling approach. Importantly, visual activity was modulated by the same stimulus parameters in younger and older subjects. The fit of the model, indexed by R2, was computed at multiple post-stimulus time points. The time-course of the R2 function showed a significantly slower processing in older observers starting around 120 ms after stimulus onset. This age-related delay increased over time to reach a maximum around 190 ms, at which latency younger observers had around 50 ms time lead over older observers. Conclusion: Using a component-free ERP analysis that provides a precise timing of the visual system sensitivity to image structure, the current study demonstrates that older observers accumulate face information more slowly than younger subjects. Additionally, the N170 appears to be less face-sensitive in older observers

The claudin gene family: expression in normal and neoplastic tissues

BACKGROUND: The claudin (CLDN) genes encode a family of proteins important in tight junction formation and function. Recently, it has become apparent that CLDN gene expression is frequently altered in several human cancers. However, the exact patterns of CLDN expression in various cancers is unknown, as only a limited number of CLDN genes have been investigated in a few tumors. METHODS: We identified all the human CLDN genes from Genbank and we used the large public SAGE database to ascertain the gene expression of all 21 CLDN in 266 normal and neoplastic tissues. Using real-time RT-PCR, we also surveyed a subset of 13 CLDN genes in 24 normal and 24 neoplastic tissues. RESULTS: We show that claudins represent a family of highly related proteins, with claudin-16, and -23 being the most different from the others. From in silico analysis and RT-PCR data, we find that most claudin genes appear decreased in cancer, while CLDN3, CLDN4, and CLDN7 are elevated in several malignancies such as those originating from the pancreas, bladder, thyroid, fallopian tubes, ovary, stomach, colon, breast, uterus, and the prostate. Interestingly, CLDN5 is highly expressed in vascular endothelial cells, providing a possible target for antiangiogenic therapy. CLDN18 might represent a biomarker for gastric cancer. CONCLUSION: Our study confirms previously known CLDN gene expression patterns and identifies new ones, which may have applications in the detection, prognosis and therapy of several human cancers. In particular we identify several malignancies that express CLDN3 and CLDN4. These cancers may represent ideal candidates for a novel therapy being developed based on CPE, a toxin that specifically binds claudin-3 and claudin-4

Improved eradication of Clostridium difficile spores from toilets of hospitalized patients using an accelerated hydrogen peroxide as the cleaning agent

<p>Abstract</p> <p>Background</p> <p><it>C. difficle </it>spores in the environment of patients with <it>C. difficile </it>associated disease (CDAD) are difficult to eliminate. Bleach (5000 ppm) has been advocated as an effective disinfectant for the environmental surfaces of patients with CDAD. Few alternatives to bleach for non-outbreak conditions have been evaluated in controlled healthcare studies.</p> <p>Methods</p> <p>This study was a prospective clinical comparison during non-outbreak conditions of the efficacy of an accelerated hydrogen peroxide cleaner (0.5% AHP) to the currently used stabilized hydrogen peroxide cleaner (0.05% SHP at manufacturer recommended use-dilution) with respect to spore removal from toilets in a tertiary care facility. The toilets used by patients who had diarrhea with and without <it>C. difficile </it>associated disease (CDAD) were cultured for <it>C. difficile </it>and were monitored using an ultraviolet mark (UVM) to assess cleaning compliance on a daily basis 5 days per week. A total of 243 patients and 714 samples were analysed. The culture results were included in the analysis only if the UVM audit from the same day confirmed that the toilet had been cleaned.</p> <p>Results</p> <p>Our data demonstrated that the efficacy of spore killing is formulation specific and cannot be generalized. The Oxivir_TB^®AHP formulation resulted in statistically significantly (p = 0.0023) lower levels of toxigenic <it>C. difficile </it>spores in toilets of patients with CDAD compared to the SHP formulation that was routinely being used (28% vs 45% culture positive). The background level of toxigenic <it>C. difficile </it>spores was 10% in toilets of patients with diarrhea not due to CDAD. The UVM audit indicated that despite the enhanced twice-daily cleaning protocol for CDAD patients cleaning was not achieved on approximately 30 - 40% of the days tested.</p> <p>Conclusion</p> <p>Our data indicate that the AHP formulation evaluated that has some sporicidal activity was significantly better than the currently used SHP formulation. This AHP formulation provides a one-step process that significantly lowers the <it>C. difficile </it>spore level in toilets during non-outbreak conditions without the workplace safety concerns associated with 5000 ppm bleach.</p

Data science

Even though it has only entered public perception relatively recently, the term "data science" already means many things to many people. This chapter explores both top-down and bottom-up views on the field, on the basis of which we define data science as "a unique blend of principles and methods from analytics, engineering, entrepreneurship and communication that aim at generating value from the data itself". The chapter then discusses the disciplines that contribute to this "blend", briefly outlining their contributions and giving pointers for readers interested in exploring their backgrounds further

The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat

PURPOSE: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of α-galactosidase A to restore lysosomal activity. METHODS: A pharmacogenetic assay was used to identify the α-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease-causing mutations were expressed in HEK-293 (HEK) cells; increases in α-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies. RESULTS: Comparison of the GLP HEK assay results in in vivo white blood cell α-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (≥0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay. CONCLUSION: The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat

Language-free graphical signage improves human performance and reduces anxiety when working collaboratively with robots

As robots become more ubiquitous, and their capabilities extend, novice users will require intuitive instructional information related to their use. This is particularly important in the manufacturing sector, which is set to be transformed under Industry 4.0 by the deployment of collaborative robots in support of traditionally low-skilled, manual roles. In the first study of its kind, this paper reports how static graphical signage can improve performance and reduce anxiety in participants physically collaborating with a semi-autonomous robot. Three groups of 30 participants collaborated with a robot to perform a manufacturing-type process using graphical information that was relevant to the task, irrelevant, or absent. The results reveal that the group exposed to relevant signage was significantly more accurate in undertaking the task. Furthermore, their anxiety towards robots significantly decreased as a function of increasing accuracy. Finally, participants exposed to graphical signage showed positive emotional valence in response to successful trials. At a time when workers are concerned about the threat posed by robots to jobs, and with advances in technology requiring upskilling of the workforce, it is important to provide intuitive and supportive information to users. Whilst increasingly sophisticated technical solutions are being sought to improve communication and confidence in human-robot co-working, our findings demonstrate how simple signage can still be used as an effective tool to reduce user anxiety and increase task performance

Crime and the NTE: multi-classification crime (MCC) hot spots in time and space

This paper examines crime hot spots near licensed premises in the night-time economy (NTE) to investigate whether hot spots of four different classification of crime and disorder co-occur in time and place, namely violence, disorder, drugs and criminal damage. It introduces the concept of multi-classification crime (MCC) hot spots; the presence of hot spots of more than one crime classification at the same place. Furthermore, it explores the temporal patterns of identified MCC hot spots, to determine if they exhibit distinct spatio-temporal patterns. Getis Ord (GI*) hot spot analysis was used to identify locations of statistically significant hot spots of each of the four crime and disorder classifications. Strong spatial correlations were found between licensed premises and each of the four crime and disorder classifications analysed. MCC hot spots were also identified near licensed premises. Temporal profiling of the MCC hot spots revealed all four crime types were simultaneously present in time and place, near licensed premises, on Friday through Sunday in the early hours of the morning around premise closing times. At other times, criminal damage and drugs hot spots were found to occur earlier in the evening, and disorder and violence at later time periods. Criminal damage and drug hot spots flared for shorter time periods, 2–3 h, whereas disorder and violence hot spots were present for several hours. There was a small spatial lag between Friday and Saturday, with offences occurring approximately 1 h later on Saturdays. The implications of these findings for hot spot policing are discussed

Deafness mutation mining using regular expression based pattern matching

<p>Abstract</p> <p>Background</p> <p>While keyword based queries of databases such as Pubmed are frequently of great utility, the ability to use regular expressions in place of a keyword can often improve the results output by such databases. Regular expressions can allow for the identification of element types that cannot be readily specified by a single keyword and can allow for different words with similar character sequences to be distinguished.</p> <p>Results</p> <p>A Perl based utility was developed to allow the use of regular expressions in Pubmed searches, thereby improving the accuracy of the searches.</p> <p>Conclusion</p> <p>This utility was then utilized to create a comprehensive listing of all DFN deafness mutations discussed in Pubmed records containing the keywords "human ear".</p

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

Stressful life events produce a state of vulnerability to depression in some individuals. The mechanisms that contribute to vulnerability to depression remain poorly understood. A rat model of intense stress (social defeat (SD), first hit) produced vulnerability to depression in 40% of animals. Only vulnerable animals developed a depression-like phenotype after a second stressful hit (chronic mild stress). We found that this vulnerability to depression resulted from a persistent state of oxidative stress, which was reversed by treatment with antioxidants. This persistent state of oxidative stress was due to low brain-derived neurotrophic factor (BDNF) levels, which characterized the vulnerable animals. We found that BDNF constitutively controlled the nuclear translocation of the master redox-sensitive transcription factor Nrf2, which activates antioxidant defenses. Low BDNF levels in vulnerable animals prevented Nrf2 translocation and consequently prevented the activation of detoxifying/antioxidant enzymes, ultimately resulting in the generation of sustained oxidative stress. Activating Nrf2 translocation restored redox homeostasis and reversed vulnerability to depression. This mechanism was confirmed in Nrf2-null mice. The mice displayed high levels of oxidative stress and were inherently vulnerable to depression, but this phenotype was reversed by treatment with antioxidants. Our data reveal a novel role for BDNF in controlling redox homeostasis and provide a mechanistic explanation for post-stress vulnerability to depression while suggesting ways to reverse it. Because numerous enzymatic reactions produce reactive oxygen species that must then be cleared, the finding that BDNF controls endogenous redox homeostasis opens new avenues for investigation