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Alzheimer’s disease (AD) is a devastating neurodegenerative condition with no known cure. While current therapies target late-stage amyloid formation and cholinergic tone, to date, these strategies have proven ineffective at preventing disease progression. The reasons for this may be varied, and could reflect late intervention, or, that earlier pathogenic mechanisms have been overlooked and permitted to accelerate the disease process. One such example would include synaptic pathology, the disease component strongly associated with cognitive impairment. Dysregulated Ca2+ homeostasis may be one of the critical factors driving synaptic dysfunction. One of the earliest pathophysiological indicators in mutant presenilin (PS) AD mice is increased intracellular Ca2+ signaling, predominantly through the ER-localized inositol triphosphate (IP3) and ryanodine receptors (RyR). In particular, the RyR-mediated Ca2+ upregulation within synaptic compartments is associated with altered synaptic homeostasis and network depression at early (presymptomatic) AD stages. Here, we offer an alternative approach to AD therapeutics by stabilizing early pathogenic mechanisms associated with synaptic abnormalities. We targeted the RyR as a means to prevent disease progression, and sub-chronically treated AD mouse models (4-weeks) with a novel formulation of the RyR inhibitor, dantrolene. Using 2-photon Ca2+ imaging and patch clamp recordings, we demonstrate that dantrolene treatment fully normalizes ER Ca2+ signaling within somatic and dendritic compartments in early and later-stage AD mice in hippocampal slices. Additionally, the elevated RyR2 levels in AD mice are restored to control levels with dantrolene treatment, as are synaptic transmission and synaptic plasticity. Aβ deposition within the cortex and hippocampus is also reduced in dantrolene-treated AD mice. In this study, we highlight the pivotal role of Ca2+ aberrations in AD, and propose a novel strategy to preserve synaptic function, and thereby cognitive function, in early AD patients.  相似文献   
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Complex coevolutionary relationships among competitors, predators, and prey have shaped taxa diversity, life history strategies, and even the avian migratory patterns we see today. Consequently, accurate documentation of prey selection is often critical for understanding these ecological and evolutionary processes. Conventional diet study methods lack the ability to document the diet of inconspicuous or difficult‐to‐study predators, such as those with large home ranges and those that move vast distances over short amounts of time, leaving gaps in our knowledge of trophic interactions in many systems. Migratory raptors represent one such group of predators where detailed diet studies have been logistically challenging. To address knowledge gaps in the foraging ecology of migrant raptors and provide a broadly applicable tool for the study of enigmatic predators, we developed a minimally invasive method to collect dietary information by swabbing beaks and talons of raptors to collect trace prey DNA. Using previously published COI primers, we were able to isolate and reference gene sequences in an open‐access barcode database to identify prey to species. This method creates a novel avenue to use trace molecular evidence to study prey selection of migrating raptors and will ultimately lead to a better understanding of raptor migration ecology. In addition, this technique has broad applicability and can be used with any wildlife species where even trace amounts of prey debris remain on the exterior of the predator after feeding.  相似文献   
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At around 7 months of age, human infants begin to reliably produce well-formed syllables containing both consonants and vowels, a behavior called canonical babbling. Over subsequent months, the frequency of canonical babbling continues to increase. How the infant’s nervous system supports the acquisition of this ability is unknown. Here we present a computational model that combines a spiking neural network, reinforcement-modulated spike-timing-dependent plasticity, and a human-like vocal tract to simulate the acquisition of canonical babbling. Like human infants, the model’s frequency of canonical babbling gradually increases. The model is rewarded when it produces a sound that is more auditorily salient than sounds it has previously produced. This is consistent with data from human infants indicating that contingent adult responses shape infant behavior and with data from deaf and tracheostomized infants indicating that hearing, including hearing one’s own vocalizations, is critical for canonical babbling development. Reward receipt increases the level of dopamine in the neural network. The neural network contains a reservoir with recurrent connections and two motor neuron groups, one agonist and one antagonist, which control the masseter and orbicularis oris muscles, promoting or inhibiting mouth closure. The model learns to increase the number of salient, syllabic sounds it produces by adjusting the base level of muscle activation and increasing their range of activity. Our results support the possibility that through dopamine-modulated spike-timing-dependent plasticity, the motor cortex learns to harness its natural oscillations in activity in order to produce syllabic sounds. It thus suggests that learning to produce rhythmic mouth movements for speech production may be supported by general cortical learning mechanisms. The model makes several testable predictions and has implications for our understanding not only of how syllabic vocalizations develop in infancy but also for our understanding of how they may have evolved.  相似文献   
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Human papillomavirus deoxyribonucleic acid was detected in prostate tissue from patients with benign prostatic hyperplasia or prostatic carcinoma. Radiolabelled genomic probes, specific for the sexually transmitted human papillomavirus types 16 and 18, were used to detect viral genomic sequences in prostate DNA samples analyzed by the Southern blot technique. Viral sequences were identified in DNA from 7 of 16 prostate samples including both hyperplastic and carcinoma tissues and including tissues obtained by transurethral resection or suprapubic prostatectomy. These data indicate that the prostate gland can be infected with human papillomavirus and imply that the prostate may act as a reservoir for the sexual transmission of papillomavirus via seminal fluid. The detection of both episomal and integrated viral DNA sequences in prostate tissue may have important implications for the etiology of prostate disease.  相似文献   
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Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) experienced severe declines due to habitat destruction and overfishing beginning in the late 19th century. Subsequent to the boom and bust period of exploitation, there has been minimal fishing pressure and improving habitats. However, lack of recovery led to the 2012 listing of Atlantic sturgeon under the Endangered Species Act. Although habitats may be improving, the availability of high quality spawning habitat, essential for the survival and development of eggs and larvae may still be a limiting factor in the recovery of Atlantic sturgeon. To estimate adult Atlantic sturgeon spatial distributions during riverine occupancy in the Delaware River, we utilized a maximum entropy (MaxEnt) approach along with passive biotelemetry during the likely spawning season. We found that substrate composition and distance from the salt front significantly influenced the locations of adult Atlantic sturgeon in the Delaware River. To broaden the scope of this study we projected our model onto four scenarios depicting varying locations of the salt front in the Delaware River: the contemporary location of the salt front during the likely spawning season, the location of the salt front during the historic fishery in the late 19th century, an estimated shift in the salt front by the year 2100 due to climate change, and an extreme drought scenario, similar to that which occurred in the 1960’s. The movement of the salt front upstream as a result of dredging and climate change likely eliminated historic spawning habitats and currently threatens areas where Atlantic sturgeon spawning may be taking place. Identifying where suitable spawning substrate and water chemistry intersect with the likely occurrence of adult Atlantic sturgeon in the Delaware River highlights essential spawning habitats, enhancing recovery prospects for this imperiled species.  相似文献   
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When the rat olfactory mucosa is treated with concanavalin A, it subsequently shows diminished sensitivity towards 60% of the 112 odorants tested (as judged by the amplitude of the electro-olfactogram response). Odorants containing four to six carbon atoms tend to show the largest (absolute) diminutions, suggesting a receptor for this kind of odorant, although the structural specificity is weak. The receptor seems to be of particular importance in the detection of thiols, carboxylic acids and hydrocarbons of the above size, since these compounds loose the highest proportion of their original signal. The concanavalin A appears to be binding to the glycan of one or more cell-surface proteins. The binding may be at, or close to, at least one odorant receptor.  相似文献   
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A phospholipid, 1,2-bis(4-(n-butyl)phenylazo-4'-phenylbutyroyl)phosphatidylcholine (Bis-Azo PC), has been synthesised and shown to form stable bilayer vesicles. Light-scattering measurements and differential scanning calorimetry show that a dispersion of the lipid has a cooperative phase transition at a similar temperature to that of dipalmitoylphosphatidylcholine, which Bis-Azo PC resembles in overall size. The phase behaviour of Bis-Azo PC has been investigated by fluorescence spectroscopy and using a series of spin-labelled fatty acid probes. Fluorescence measurements using chlorophyll a as probe sense the onset of the cooperative phase transition, but this is not clearly revealed by any of the spin probes tested. Hysteresis in the phase transition is detected both by light scattering measurements and by fluorescence spectroscopy. No transition is observed for a lipid analogue having a palmitic acid chain and a single azo-containing substituent. Bis-Azo PC is reversibly photochromic, isomerising on exposure to ultraviolet light to a photostationary state mixture where cis isomer predominates. Electron microscopy shows that photoisomerisation decreases average vesicle size, and light scattering and calorimetry demonstrate that the cooperative phase transition is abolished. Illumination with visible light establishes a new photostationary state where trans isomer predominates, and the phase transition is restored. The ability to modulate bilayer phase behaviour reversibly has possible application to relaxation studies of bilayer membrane function, and to drug delivery research.  相似文献   
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For certain odorants, the amplitude of the rat electro-olfactogram is reduced if the olfactory epithelium is treated with the lectin concanavalin A. When normal and cycloalkanes of one to ten carbon atoms are used as odorants at equimolar concentration, the maximum reduction in amplitude is found to correlate with the size of the stimulus molecule. This observation is consistent with the notion that concanavalin A disables an olfactory receptor molecule which normally responds to the alkyl moiety of odorants in a particular size range. That moiety may thus represent a 'primary' quality-determining component in odour discrimination.  相似文献   
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