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1.  Immunogenicity, Efficacy, Safety, and Mechanism of Action of Epitope Vaccine (Lu AF20513) for Alzheimer’s Disease: Prelude to a Clinical Trial 
Alzheimer’s disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aβ peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aβ antibodies failed to slow cognitive decline in mild-moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. In an AD mouse model (Tg2576) we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. Lu AF20513 induces robust “non-self” T cell responses and production of anti-Aβ antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or CAA. Importantly, a single immunization with Lu AF20513 induces strong humoral immunity in mice with pre-existing memory Th cells. In addition, Lu AF20513 induces strong humoral responses in guinea pigs and monkeys. Collectively, these data suggest translation of Lu AF20513 to clinical setting with aims to (i) induce therapeutically potent anti-Aβ antibody responses in patients with mild AD, particularly if they have memory Th cells generated after immunizations with conventional Tetanus Toxoid vaccine; (ii) exclude likely pathological autoreactive T cell responses.
doi:10.1523/JNEUROSCI.4672-12.2013
PMCID: PMC3634356  PMID: 23486963
2.  Ultrasonic predator–prey interactions in water–convergent evolution with insects and bats in air? 
Toothed whales and bats have independently evolved biosonar systems to navigate and locate and catch prey. Such active sensing allows them to operate in darkness, but with the potential cost of warning prey by the emission of intense ultrasonic signals. At least six orders of nocturnal insects have independently evolved ears sensitive to ultrasound and exhibit evasive maneuvers when exposed to bat calls. Among aquatic prey on the other hand, the ability to detect and avoid ultrasound emitting predators seems to be limited to only one subfamily of Clupeidae: the Alosinae (shad and menhaden). These differences are likely rooted in the different physical properties of air and water where cuticular mechanoreceptors have been adapted to serve as ultrasound sensitive ears, whereas ultrasound detection in water have called for sensory cells mechanically connected to highly specialized gas volumes that can oscillate at high frequencies. In addition, there are most likely differences in the risk of predation between insects and fish from echolocating predators. The selection pressure among insects for evolving ultrasound sensitive ears is high, because essentially all nocturnal predation on flying insects stems from echolocating bats. In the interaction between toothed whales and their prey the selection pressure seems weaker, because toothed whales are by no means the only marine predators placing a selection pressure on their prey to evolve specific means to detect and avoid them. Toothed whales can generate extremely intense sound pressure levels, and it has been suggested that they may use these to debilitate prey. Recent experiments, however, show that neither fish with swim bladders, nor squid are debilitated by such signals. This strongly suggests that the production of high amplitude ultrasonic clicks serve the function of improving the detection range of the toothed whale biosonar system rather than debilitation of prey.
doi:10.3389/fphys.2013.00137
PMCID: PMC3679510  PMID: 23781206
predator–prey interaction; echolocation; ultrasound; toothed whale; Alosinae; bat; moth; evasivemaneuvers
3.  Clicking in a Killer Whale Habitat: Narrow-Band, High-Frequency Biosonar Clicks of Harbour Porpoise (Phocoena phocoena) and Dall’s Porpoise (Phocoenoides dalli) 
PLoS ONE  2013;8(5):e63763.
Odontocetes produce a range of different echolocation clicks but four groups in different families have converged on producing the same stereotyped narrow band high frequency (NBHF) click. In microchiropteran bats, sympatric species have evolved the use of different acoustic niches and subtly different echolocation signals to avoid competition among species. In this study, we examined whether similar adaptations are at play among sympatric porpoise species that use NBHF echolocation clicks. We used a six-element hydrophone array to record harbour and Dall’s porpoises in British Columbia (BC), Canada, and harbour porpoises in Denmark. The click source properties of all porpoise groups were remarkably similar and had an average directivity index of 25 dB. Yet there was a small, but consistent and significant 4 kHz difference in centroid frequency between sympatric Dall’s (137±3 kHz) and Canadian harbour porpoises (141±2 kHz). Danish harbour porpoise clicks (136±3 kHz) were more similar to Dall’s porpoise than to their conspecifics in Canada. We suggest that the spectral differences in echolocation clicks between the sympatric porpoises are consistent with evolution of a prezygotic isolating barrier (i.e., character displacement) to avoid hybridization of sympatric species. In practical terms, these spectral differences have immediate application to passive acoustic monitoring.
doi:10.1371/journal.pone.0063763
PMCID: PMC3665716  PMID: 23723996
4.  Clicking in Shallow Rivers: Short-Range Echolocation of Irrawaddy and Ganges River Dolphins in a Shallow, Acoustically Complex Habitat 
PLoS ONE  2013;8(4):e59284.
Toothed whales (Cetacea, odontoceti) use biosonar to navigate their environment and to find and catch prey. All studied toothed whale species have evolved highly directional, high-amplitude ultrasonic clicks suited for long-range echolocation of prey in open water. Little is known about the biosonar signals of toothed whale species inhabiting freshwater habitats such as endangered river dolphins. To address the evolutionary pressures shaping the echolocation signal parameters of non-marine toothed whales, we investigated the biosonar source parameters of Ganges river dolphins (Platanista gangetica gangetica) and Irrawaddy dolphins (Orcaella brevirostris) within the river systems of the Sundarban mangrove forest. Both Ganges and Irrawaddy dolphins produced echolocation clicks with a high repetition rate and low source level compared to marine species. Irrawaddy dolphins, inhabiting coastal and riverine habitats, produced a mean source level of 195 dB (max 203 dB) re 1 µPapp whereas Ganges river dolphins, living exclusively upriver, produced a mean source level of 184 dB (max 191) re 1 µPapp. These source levels are 1–2 orders of magnitude lower than those of similar sized marine delphinids and may reflect an adaptation to a shallow, acoustically complex freshwater habitat with high reverberation and acoustic clutter. The centroid frequency of Ganges river dolphin clicks are an octave lower than predicted from scaling, but with an estimated beamwidth comparable to that of porpoises. The unique bony maxillary crests found in the Platanista forehead may help achieve a higher directionality than expected using clicks nearly an octave lower than similar sized odontocetes.
doi:10.1371/journal.pone.0059284
PMCID: PMC3616034  PMID: 23573197
5.  High Source Levels and Small Active Space of High-Pitched Song in Bowhead Whales (Balaena mysticetus) 
PLoS ONE  2012;7(12):e52072.
The low-frequency, powerful vocalizations of blue and fin whales may potentially be detected by conspecifics across entire ocean basins. In contrast, humpback and bowhead whales produce equally powerful, but more complex broadband vocalizations composed of higher frequencies that suffer from higher attenuation. Here we evaluate the active space of high frequency song notes of bowhead whales (Balaena mysticetus) in Western Greenland using measurements of song source levels and ambient noise. Four independent, GPS-synchronized hydrophones were deployed through holes in the ice to localize vocalizing bowhead whales, estimate source levels and measure ambient noise. The song had a mean apparent source level of 185±2 dB rms re 1 µPa @ 1 m and a high mean centroid frequency of 444±48 Hz. Using measured ambient noise levels in the area and Arctic sound spreading models, the estimated active space of these song notes is between 40 and 130 km, an order of magnitude smaller than the estimated active space of low frequency blue and fin whale songs produced at similar source levels and for similar noise conditions. We propose that bowhead whales spatially compensate for their smaller communication range through mating aggregations that co-evolved with broadband song to form a complex and dynamic acoustically mediated sexual display.
doi:10.1371/journal.pone.0052072
PMCID: PMC3530606  PMID: 23300591
6.  Calling under pressure: short-finned pilot whales make social calls during deep foraging dives 
Toothed whales rely on sound to echolocate prey and communicate with conspecifics, but little is known about how extreme pressure affects pneumatic sound production in deep-diving species with a limited air supply. The short-finned pilot whale (Globicephala macrorhynchus) is a highly social species among the deep-diving toothed whales, in which individuals socialize at the surface but leave their social group in pursuit of prey at depths of up to 1000 m. To investigate if these animals communicate acoustically at depth and test whether hydrostatic pressure affects communication signals, acoustic DTAGs logging sound, depth and orientation were attached to 12 pilot whales. Tagged whales produced tonal calls during deep foraging dives at depths of up to 800 m. Mean call output and duration decreased with depth despite the increased distance to conspecifics at the surface. This shows that the energy content of calls is lower at depths where lungs are collapsed and where the air volume available for sound generation is limited by ambient pressure. Frequency content was unaffected, providing a possible cue for group or species identification of diving whales. Social calls may be important to maintain social ties for foraging animals, but may be impacted adversely by vessel noise.
doi:10.1098/rspb.2010.2604
PMCID: PMC3158928  PMID: 21345867
communication; sound production; social organization; pilot whales; acoustic tags; ecophysiology
7.  Correction: Following a Foraging Fish-Finder: Diel Habitat Use of Blainville's Beaked Whales Revealed by Echolocation 
PLoS ONE  2012;7(3):10.1371/annotation/49be01ca-99fb-40f2-bb9c-9720c87be632.
doi:10.1371/annotation/49be01ca-99fb-40f2-bb9c-9720c87be632
PMCID: PMC3319701
8.  Specialization for underwater hearing by the tympanic middle ear of the turtle, Trachemys scripta elegans 
Turtles, like other amphibious animals, face a trade-off between terrestrial and aquatic hearing. We used laser vibrometry and auditory brainstem responses to measure their sensitivity to vibration stimuli and to airborne versus underwater sound. Turtles are most sensitive to sound underwater, and their sensitivity depends on the large middle ear, which has a compliant tympanic disc attached to the columella. Behind the disc, the middle ear is a large air-filled cavity with a volume of approximately 0.5 ml and a resonance frequency of approximately 500 Hz underwater. Laser vibrometry measurements underwater showed peak vibrations at 500–600 Hz with a maximum of 300 µm s−1 Pa−1, approximately 100 times more than the surrounding water. In air, the auditory brainstem response audiogram showed a best sensitivity to sound of 300–500 Hz. Audiograms before and after removing the skin covering reveal that the cartilaginous tympanic disc shows unchanged sensitivity, indicating that the tympanic disc, and not the overlying skin, is the key sound receiver. If air and water thresholds are compared in terms of sound intensity, thresholds in water are approximately 20–30 dB lower than in air. Therefore, this tympanic ear is specialized for underwater hearing, most probably because sound-induced pulsations of the air in the middle ear cavity drive the tympanic disc.
doi:10.1098/rspb.2012.0290
PMCID: PMC3367789  PMID: 22438494
underwater sound; evolution; cochlea; auditory brainstem response
9.  Hearing in the African lungfish (Protopterus annectens): pre-adaptation to pressure hearing in tetrapods? 
Biology Letters  2010;7(1):139-141.
Lungfishes are the closest living relatives of the tetrapods, and the ear of recent lungfishes resembles the tetrapod ear more than the ear of ray-finned fishes and is therefore of interest for understanding the evolution of hearing in the early tetrapods. The water-to-land transition resulted in major changes in the tetrapod ear associated with the detection of air-borne sound pressure, as evidenced by the late and independent origins of tympanic ears in all of the major tetrapod groups. To investigate lungfish pressure and vibration detection, we measured the sensitivity and frequency responses of five West African lungfish (Protopterus annectens) using brainstem potentials evoked by calibrated sound and vibration stimuli in air and water. We find that the lungfish ear has good low-frequency vibration sensitivity, like recent amphibians, but poor sensitivity to air-borne sound. The skull shows measurable vibrations above 100 Hz when stimulated by air-borne sound, but the ear is apparently insensitive at these frequencies, suggesting that the lungfish ear is neither adapted nor pre-adapted for aerial hearing. Thus, if the lungfish ear is a model of the ear of early tetrapods, their auditory sensitivity was limited to very low frequencies on land, mostly mediated by substrate-borne vibrations.
doi:10.1098/rsbl.2010.0636
PMCID: PMC3030901  PMID: 20826468
lungfish; hearing; vibration; tetrapod; sound; evolution
10.  Correction: Following a Foraging Fish-Finder: Diel Habitat Use of Blainville's Beaked Whales Revealed by Echolocation 
PLoS ONE  2012;7(1):10.1371/annotation/c165133f-34fd-4cca-b84f-fc30de881332.
doi:10.1371/annotation/c165133f-34fd-4cca-b84f-fc30de881332
PMCID: PMC3251628
11.  Following a Foraging Fish-Finder: Diel Habitat Use of Blainville's Beaked Whales Revealed by Echolocation 
PLoS ONE  2011;6(12):e28353.
Simultaneous high resolution sampling of predator behavior and habitat characteristics is often difficult to achieve despite its importance in understanding the foraging decisions and habitat use of predators. Here we tap into the biosonar system of Blainville's beaked whales, Mesoplodon densirostris, using sound and orientation recording tags to uncover prey-finding cues available to echolocating predators in the deep-sea. Echolocation sounds indicate where whales search and encounter prey, as well as the altitude of whales above the sea-floor and the density of organisms around them, providing a link between foraging activity and the bio-physical environment. Tagged whales (n = 9) hunted exclusively at depth, investing most of their search time either in the lower part of the deep scattering layer (DSL) or near the sea-floor with little diel change. At least 43% (420/974) of recorded prey-capture attempts were performed within the benthic boundary layer despite a wide range of dive depths, and many dives included both meso- and bentho-pelagic foraging. Blainville's beaked whales only initiate searching when already deep in the descent and encounter prey suitable for capture within 2 min of the start of echolocation, suggesting that these whales are accessing prey in reliable vertical strata. Moreover, these prey resources are sufficiently dense to feed the animals in what is effectively four hours of hunting per day enabling a strategy in which long dives to exploit numerous deep-prey with low nutritional value require protracted recovery periods (average 1.5 h) between dives. This apparent searching efficiency maybe aided by inhabiting steep undersea slopes with access to both the DSL and the sea-floor over small spatial scales. Aggregations of prey in these biotopes are located using biosonar-derived landmarks and represent stable and abundant resources for Blainville's beaked whales in the otherwise food-limited deep-ocean.
doi:10.1371/journal.pone.0028353
PMCID: PMC3233560  PMID: 22163295
12.  Behaviour and kinematics of continuous ram filtration in bowhead whales (Balaena mysticetus) 
Balaenid whales perform long breath-hold foraging dives despite a high drag from their ram filtration of zooplankton. To maximize the volume of prey acquired in a dive with limited oxygen supplies, balaenids must either filter feed only occasionally when prey density is particularly high, or they must swim at slow speeds while filtering to reduce drag and oxygen consumption. Using digital tags with three-axis accelerometers, we studied bowhead whales feeding off West Greenland and present here, to our knowledge, the first detailed data on the kinematics and swimming behaviour of a balaenid whale filter feeding at depth. Bowhead whales employ a continuous fluking gait throughout the bottom phase of foraging dives, moving at very slow speeds (less than 1 m s−1), allowing them to filter feed continuously at depth. Despite the slow speeds, the large mouth aperture provides a water filtration rate of approximately 3 m3 s−1, amounting to some 2000 tonnes of water and prey filtered per dive. We conclude that a food niche of dense, slow-moving zooplankton prey has led balaenids to evolve locomotor and filtering systems adapted to work against a high drag at swimming speeds of less than 0.07 body length s−1 using a continuous fluking gait very different from that of nekton-feeding, aquatic predators.
doi:10.1098/rspb.2009.1135
PMCID: PMC2817290  PMID: 19692400
filter feeding; bowhead whale; kinematics
13.  Intense ultrasonic clicks from echolocating toothed whales do not elicit anti-predator responses or debilitate the squid Loligo pealeii 
Biology Letters  2007;3(3):225-227.
Toothed whales use intense ultrasonic clicks to echolocate prey and it has been hypothesized that they also acoustically debilitate their prey with these intense sound pulses to facilitate capture. Cephalopods are an important food source for toothed whales, and there has probably been an evolutionary selection pressure on cephalopods to develop a mechanism for detecting and evading sound-emitting toothed whale predators. Ultrasonic detection has evolved in some insects to avoid echolocating bats, and it can be hypothesized that cephalopods might have evolved similar ultrasound detection as an anti-predation measure. We test this hypothesis in the squid Loligo pealeii in a playback experiment using intense echolocation clicks from two squid-eating toothed whale species. Twelve squid were exposed to clicks at two repetition rates (16 and 125 clicks per second) with received sound pressure levels of 199–226 dB re 1 μPa (pp) mimicking the sound exposure from an echolocating toothed whale as it approaches and captures prey. We demonstrate that intense ultrasonic clicks do not elicit any detectable anti-predator behaviour in L. pealeii and that clicks with received levels up to 226 dB re 1 μPa (pp) do not acoustically debilitate this cephalopod species.
doi:10.1098/rsbl.2007.0005
PMCID: PMC2464686  PMID: 17412672
squid; toothed whales; echolocation; predation; defence
14.  Beaked whales echolocate on prey. 
Beaked whales (Cetacea: Ziphiidea) of the genera Ziphius and Mesoplodon are so difficult to study that they are mostly known from strandings. How these elusive toothed whales use and react to sound is of concern because they mass strand during naval sonar exercises. A new non-invasive acoustic ording tag was attached to four beaked whales(two Mesoplodon densirostris and two Ziphius cavirostris) and recorded high-frequency clicks during deep dives. The tagged whales only clicked at depths below 200 m, down to a maximum depth of 1267 m. Both species produced a large number of short, directional, ultrasonic clicks with significant energy below 20 kHz. The tags recorded echoes from prey items; to our knowledge, a first for any animal echolocating in the wild. As far as we are aware, these echoes provide the first direct evidence on how free-ranging toothed whales use echolocation in foraging. The strength of these echoes suggests that the source level of Mesoplodon clicks is in the range of 200-220 dB re 1 microPa at 1 m.This paper presents conclusive data on the normal vocalizations of these beaked whale species, which may enable acoustic monitoring to mitigate exposure to sounds intense enough to harm them.
PMCID: PMC1810096  PMID: 15801582
15.  Constitutive Expression of a Transcription Termination Factor by a Repressed Prophage: Promoters for Transcribing the Phage HK022 nun Gene 
Journal of Bacteriology  2000;182(2):456-462.
Lysogens of phage HK022 are resistant to infection by phage λ. Lambda resistance is caused by the action of the HK022 Nun protein, which prematurely terminates early λ transcripts. We report here that transcription of the nun gene initiates at a constitutive prophage promoter, PNun, located just upstream of the protein coding sequence. The 5′ end of the transcript was determined by primer extension analysis of RNA isolated from HK022 lysogens or RNA made in vitro by transcribing a template containing the promoter with purified Escherichia coli RNA polymerase. Inactivation of PNun by mutation greatly reduced Nun activity and Nun antigen in an HK022 lysogen. However, a low level of residual activity was detected, suggesting that a secondary promoter also contributes to nun expression. We found one possible secondary promoter, PNun′, just upstream of PNun. Neither promoter is likely to increase the expression of other phage genes in a lysogen because their transcripts should be terminated downstream of nun. We estimate that HK022 lysogens in stationary phase contain several hundred molecules of Nun per cell and that cells in exponential phase probably contain fewer.
PMCID: PMC94296  PMID: 10629193
16.  The Genetic Switch Regulating Activity of Early Promoters of the Temperate Lactococcal Bacteriophage TP901-1 
Journal of Bacteriology  1999;181(24):7430-7438.
A functional analysis of open reading frame 4 (ORF4) and ORF5 from the temperate lactococcal phage TP901-1 was performed by mutant and deletion analysis combined with transcriptional studies of the early phage promoters pR and pL. ORF4 (180 amino acids) was identified as a phage repressor necessary for repression of both promoters. Furthermore, the presence of ORF4 confers immunity of the host strain to TP901-1. ORF5 (72 amino acids) was found to be able to inhibit repression of the lytic promoter pL by ORF4. Upon transformation with a plasmid containing both ORF4 and ORF5 and their cognate promoters, clonal variation is observed: in each transformant, either pL is open and pR is closed or vice versa. The repression is still dependent on ORF4, and the presence of ORF5 is needed for the clonal variation. Induction of a repressed pL fusion containing orf4 and orf5 was obtained by addition of mitomycin C, and the induction was also shown to be dependent on the presence of the RecA protein, even though ORF4 does not contain a recognizable autocleavage site. Our results suggest that the relative amounts of the two proteins ORF4 and ORF5 determine the decision between lytic or lysogenic life cycle after phage infection and that a protein complex consisting of ORF4 and ORF5 may constitute a new type of genetic switch in bacteriophages.
PMCID: PMC94198  PMID: 10601198
17.  Degradation of Phthalate and Di-(2-Ethylhexyl)phthalate by Indigenous and Inoculated Microorganisms in Sludge-Amended Soil 
Applied and Environmental Microbiology  1998;64(12):4711-4719.
The metabolism of phthalic acid (PA) and di-(2-ethylhexyl)phthalate (DEHP) in sludge-amended agricultural soil was studied with radiotracer techniques. The initial rates of metabolism of PA and DEHP (4.1 nmol/g [dry weight]) were estimated to be 731.8 and 25.6 pmol/g (dry weight) per day, respectively. Indigenous microorganisms assimilated 28 and 17% of the carbon in [14C]PA and [14C]DEHP, respectively, into microbial biomass. The rates of DEHP metabolism were much greater in sludge assays without soil than in assays with sludge-amended soil. Mineralization of [14C]DEHP to 14CO2 increased fourfold after inoculation of sludge and soil samples with DEHP-degrading strain SDE 2. The elevated mineralization potential was maintained for more than 27 days. Experiments performed with strain SDE 2 suggested that the bioavailability and mineralization of DEHP decreased substantially in the presence of soil and sludge components. The microorganisms metabolizing PA and DEHP in sludge and sludge-amended soil were characterized by substrate-specific radiolabelling, followed by analysis of 14C-labelled phospholipid ester-linked fatty acids (14C-PLFAs). This assay provided a radioactive fingerprint of the organisms actively metabolizing [14C]PA and [14C]DEHP. The 14C-PLFA fingerprints showed that organisms with different PLFA compositions metabolized PA and DEHP in sludge-amended soil. In contrast, microorganisms with comparable 14C-PLFA fingerprints were found to dominate DEHP metabolism in sludge and sludge-amended soil. Our results suggested that indigenous sludge microorganisms dominated DEHP degradation in sludge-amended soil. Mineralization of DEHP and PA followed complex kinetics that could not be described by simple first-order equations. The initial mineralization activity was described by an exponential function; this was followed by a second phase that was described best by a fractional power function. In the initial phase, the half times for PA and DEHP in sludge-amended soil were 2 and 58 days, respectively. In the late phase of incubation, the apparent half times for PA and DEHP increased to 15 and 147 days, respectively. In the second phase (after more than 28 days), the half time for DEHP was 2.9 times longer in sludge-amended soil assays than in sludge assays without soil. Experiments with radiolabelled DEHP degraders suggested that a significant fraction of the 14CO2 produced in long-term degradation assays may have originated from turnover of labelled microbial biomass rather than mineralization of [14C]PA or [14C]DEHP. It was estimated that a significant amount of DEHP with poor biodegradability and extractability remains in sludge-amended soil for extended periods of time despite the presence of microorganisms capable of degrading the compound (e.g., more than 40% of the DEHP added is not mineralized after 1 year).
PMCID: PMC90913  PMID: 9835553

Results 1-17 (17)