In-vivo kinetics of inhaled 5-Aminolevulinic acid-Induced Protoporphyrin IX fluorescence in bronchial tissue

BACKGROUND: In the diagnosis of early-stage lung cancer photosensitizer-enhanced fluorescence bronchoscopy with inhaled 5-aminolevolinic acid (5-ALA) increases sensitivity when compared to white-light bronchoscopy. This investigation was to evaluate the in vivo tissue pharmacokinetics of inhaled 5-ALA within the bronchial mucosa in order to define the time optimum for its application prior to bronchoscopy. METHODS: Patients with known or suspected bronchial carcinoma were randomized to receive 200 mg 5-ALA via inhalation 1, 2, 3, 4 or 6 hours before flexible fluorescence bronchoscopy was performed. Macroscopically suspicious areas as well as areas with visually detected porphyrin fluorescence and normal control sites were measured spectroscopically. Biopsies for histopathology were obtained from suspicious areas as well as from adjacent normal areas. RESULTS: Fluorescence bronchoscopy performed in 19 patients reveals a sensitivity for malignant and premalignant changes (moderate dysplasia) which is almost twice as high as that of white-light bronchoscopy, whereas specificity is reduced. This is due to false-positive inflammatory lesions which also frequently show increased porphyrin fluorescence. Malignant and premalignant alterations produced fluorescence values that are up to 5 times higher than those of normal tissue. According to the pharmacokinetics of porphyrin fluorescence measured by spectroscopy, the optimum time range for 5-ALA application is 80–270 min prior to fluorescence bronchoscopy, with an optimum at 160 min. CONCLUSION: According to our results we propose inhalation of 5-ALA 160 min prior to fluorescence bronchoscopy, suggesting that this time difference provides the best tumor/normal tissue fluorescence ratio

Risk‐sensitive planning for conserving coral reefs under rapid climate change

Coral reef ecosystems are seriously threatened by changing conditions in the ocean. Although many factors are implicated, climate change has emerged as a dominant and rapidly growing threat. Developing a long‐term strategic plan for the conservation of coral reefs is urgently needed yet is complicated by significant uncertainty associated with climate change impacts on coral reef ecosystems. We use Modern Portfolio Theory to identify coral reef locations globally that, in the absence of other impacts, are likely to have a heightened chance of surviving projected climate changes relative to other reefs. Long‐term planning that is robust to uncertainty in future conditions provides an objective and transparent framework for guiding conservation action and strategic investment. These locations constitute important opportunities for novel conservation investments to secure less vulnerable yet well‐connected coral reefs that may, in turn, help to repopulate degraded areas in the event that the climate has stabilized

On effective actions of BPS branes and their higher derivative corrections

We calculate in detail the disk level S-matrix element of one Ramond-Ramond field and three gauge field vertex operators in the world volume of BPS branes, to find four gauge field couplings to all orders of $\alpha'$ up to on-shell ambiguity. Then using these infinite couplings we find that the massless pole of the field theory amplitude is exactly equal to the massless pole S-matrix element of this amplitude for the $p=n$ case to all orders of $\alpha'$. Finally we show that the infinite massless poles and the contact terms of this amplitude for the $p=n+2$ case can be reproduced by the Born-Infeld action and the Wess-Zumino actions and by their higher derivative corrections.Comment: 26 pages, 2 figures, minor corrections,references added and version published in JHE

Mutations in protocadherin 15 and cadherin 23 affect tip links and mechanotransduction in mammalian sensory hair cells

Immunocytochemical studies have shown that protocadherin-15 (PCDH15) and cadherin-23 (CDH23) are associated with tip links, structures thought to gate the mechanotransducer channels of hair cells in the sensory epithelia of the inner ear. The present report describes functional and structural analyses of hair cells from Pcdh15av3J (av3J), Pcdh15av6J (av6J) and Cdh23v2J (v2J) mice. The av3J and v2J mice carry point mutations that are predicted to introduce premature stop codons in the transcripts for Pcdh15 and Cdh23, respectively, and av6J mice have an in-frame deletion predicted to remove most of the 9th cadherin ectodomain from PCDH15. Severe disruption of hair-bundle morphology is observed throughout the early-postnatal cochlea in av3J/av3J and v2J/v2J mice. In contrast, only mild-to-moderate bundle disruption is evident in the av6J/av6J mice. Hair cells from av3J/av3J mice are unaffected by aminoglycosides and fail to load with [3H]-gentamicin or FM1-43, compounds that permeate the hair cell's mechanotransducer channels. In contrast, hair cells from av6J/av6J mice load with both FM1-43 and [3H]-gentamicin, and are aminoglycoside sensitive. Transducer currents can be recorded from hair cells of all three mutants but are reduced in amplitude in all mutants and have abnormal directional sensitivity in the av3J/av3J and v2J/v2J mutants. Scanning electron microscopy of early postnatal cochlear hair cells reveals tip-link like links in av6J/av6J mice, substantially reduced numbers of links in the av3J/av3J mice and virtually none in the v2J/v2J mice. Analysis of mature vestibular hair bundles reveals an absence of tip links in the av3J/av3J and v2J/v2J mice and a reduction in av6J/av6J mice. These results therefore provide genetic evidence consistent with PCDH15 and CDH23 being part of the tip-link complex and necessary for normal mechanotransduction

FtsK-Dependent Dimer Resolution on Multiple Chromosomes in the Pathogen Vibrio cholerae

Unlike most bacteria, Vibrio cholerae harbors two distinct, nonhomologous circular chromosomes (chromosome I and II). Many features of chromosome II are plasmid-like, which raised questions concerning its chromosomal nature. Plasmid replication and segregation are generally not coordinated with the bacterial cell cycle, further calling into question the mechanisms ensuring the synchronous management of chromosome I and II. Maintenance of circular replicons requires the resolution of dimers created by homologous recombination events. In Escherichia coli, chromosome dimers are resolved by the addition of a crossover at a specific site, dif, by two tyrosine recombinases, XerC and XerD. The process is coordinated with cell division through the activity of a DNA translocase, FtsK. Many E. coli plasmids also use XerCD for dimer resolution. However, the process is FtsK-independent. The two chromosomes of the V. cholerae N16961 strain carry divergent dimer resolution sites, dif1 and dif2. Here, we show that V. cholerae FtsK controls the addition of a crossover at dif1 and dif2 by a common pair of Xer recombinases. In addition, we show that specific DNA motifs dictate its orientation of translocation, the distribution of these motifs on chromosome I and chromosome II supporting the idea that FtsK translocation serves to bring together the resolution sites carried by a dimer at the time of cell division. Taken together, these results suggest that the same FtsK-dependent mechanism coordinates dimer resolution with cell division for each of the two V. cholerae chromosomes. Chromosome II dimer resolution thus stands as a bona fide chromosomal process

Human exposures to by-products from animals suspected to have died of anthrax in Bangladesh: An exploratory study

Anthrax is a zoonotic disease caused by the bacterium Bacillus anthracis that is considered endemic in Bangladesh, where cases among animals and people have been reported almost annually since 2009. Contaminated by-products from animals are suspected to play a role in transmission to people, but minimal information is known on the supply chain of these potentially contaminated products. Between April 2013 and May 2016, we conducted a qualitative study in 17 villages located in five districts in Bangladesh, which had experienced suspected anthrax outbreaks. The study explored how by-products from suspected animal cases were collected, discarded, processed, distributed and used by people. We conducted open-ended interviews, group discussions and unstructured observations of people's exposure to animal by-products. The practice of slaughtering acutely ill domestic ruminants before they died was common. Respondents reported that moribund animals were typically butchered, and the waste products were discarded in nearby rivers, ditches, bamboo bushes, or on privately owned land. Regardless of health status before death, very few carcasses were buried, and none were incinerated or burned. The hides were reportedly used to make wallets, belts, shoes, balls and clothing. Discarded bones were often ground into granular and powder forms to produce bone meal and fertilizer. Therefore, given anthrax is endemic in the study region, livestock with acute onset of fatal disease or found dead with no known cause of death may be an anthrax case and subsequently pose a health risk to those involved in the collection and processing of the carcass, as well as the end-user of these products. Improved bio-security practices and safe carcass disposal measures could reduce the risk of human exposure, but resource and other constraints make implementation a challenge. Therefore, targeting at-risk animal populations for vaccination may be the most effective strategy to reduce anthrax outbreaks, protect the supply chain and reduce the risk of exposure to B. anthracis

Seeing is believing: the nocturnal malarial mosquito Anopheles coluzzii responds to visual host-cues when odour indicates a host is nearby

Background: The immediate aim of our study was to analyse the behaviour of the malarial mosquito Anopheles coluzzii (An. gambiae species complex) near a human host with the ultimate aim of contributing to our fundamental understanding of mosquito host-seeking behaviour and the overall aim of identifying behaviours that could be exploited to enhance sampling and control strategies. Results: Based on 3D video recordings of individual host-seeking females in a laboratory wind-tunnel, we found that despite being a nocturnal species, An. coluzzii is highly responsive to a visually conspicuous object, but only in the presence of host-odour. Female mosquitoes approached and abruptly veered away from a dark object, which suggests attraction to visual cues plays a role in bringing mosquitoes to the source of host odour. It is worth noting that the majority of our recorded flight tracks consisted of highly stereotyped ‘dipping’ sequences near the ground, which have been mentioned in the literature, but never before quantified. Conclusions: Our quantitative analysis of female mosquito flight patterns within ~1.5 m of a host has revealed highly relevant information about responsiveness to visual objects and flight height that could revolutionise the efficacy of sampling traps; the capturing device of a trap should be visually conspicuous and positioned near the ground where the density of host-seeking mosquitoes would be greatest. These characteristics are not universally present in current traps for malarial mosquitoes. The characterisation of a new type of flight pattern that is prevalent in mosquitoes suggests that there is still much that is not fully understood about mosquito flight behaviour