Stabilizing ER Ca2+ Channel Function as an Early Preventative Strategy for Alzheimer’s Disease

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.     

New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS.

The genetics of resistance to infection by HIV-1 cohort consists of 200 slow and 75 rapid progressors to AIDS corresponding to the extremes of HIV disease outcome of 20,000 Caucasians of European descent. A comprehensive analysis of HLA class I and class II genes in this highly informative cohort has identified HLA alleles associated with fast or slow progression, including several not described previously. A quantitative analysis shows an overall HLA influence independent of and equal in magnitude (for the protective effect) to the effect of the CCR5-Delta32 mutation. Among HLA class I genes, A29 (p = 0.001) and B22 (p < 0.0001) are significantly associated with rapid progression, whereas B14 (p = 0.001) and C8 (p = 0.004) are significantly associated with nonprogression. The class I alleles B27, B57, C14 (protective), and C16, as well as B35 (susceptible), are also influential, but their effects are less robust. Influence of class II alleles was only observed for DR11. These results confirm the influence of the immune system on disease progression and may have implications on peptide-based vaccine development.     

The effects of p-mercuribenzenesulfonate on purified spectrin and actin

The compound p-mercuribenzenefulfonate was found to affect the self-association behavior of both spectrin and actin. The reagent brings about the depolymerization of F-actin, as judged from the decrease in the fluorescence of an attached pyrene label, with a second-order rate constant an order of magnitude less than that for the disruption of isolated erythrocyte cytoskeletons. Therefore, it is unlikely that the depolymerization of actin is the rate-determining step in the mercurial-dependent disruption of the erythrocyte cytoskeleton. Low reagent concentrations caused an initial rapid dissociation of spectrin tetramers at a rate comparable with that of cytoskeleton disruption. Prolonged incubation, or higher reagent concentrations, resulted in subsequent aggregation of spectrin. The reagent also prevented the interaction between spectrin and actin, presumably through its depolymerization of actin and its effects on spectrin. The early event in the disruption of isolated erythrocyte cytoskeletons by p-mercuribenzenesulfonate thus appears to be the dissociation of spectrin oligomers. Subsequent depolymerization of actin brought about by the reagent then results in total disruption of the cytoskeleton.     

Messy eaters: Swabbing prey DNA from the exterior of inconspicuous predators when foraging cannot be observed

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.     

Learning to Produce Syllabic Speech Sounds via Reward-Modulated Neural Plasticity

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.     

Long‐term population dynamics of a coral reef gastropod and responses to disturbance

The age‐specific density of the red‐lipped stromb Strombus luhuanus (Mollusca: Gastropoda) was monitored over 13 years (1981–1993) at four locations on the intertidal reef flat at Heron Island, Great Barrier Reef. Densities were highly variable, but there were persistent, location‐specific differences in population density, age structure and adult body size, the latter indicating that the populations were not extensively linked by adult movement. There was relatively high recruitment at most locations in 1984, 1989 and 1993, each occurring approximately 2 years after El Niño/Southern Oscillation events, although recruit density during these years varied in both space and time. The studied strombs experienced three disturbance events: (i) experimental harvesting at two locations (1984–1985); (ii) siltation from a harbour dredging operation (1987–1988); and (iii) a severe cyclone (1992). Resilience to harvesting at a local scale (0.5–2 ha) was high: density had recovered within a year, due to immigration of adults and older juveniles. Strombus luhuanus responded much more strongly to broad‐scale changes to its environment than to localized harvesting. After dredging, there was a progressive density decline coupled with low recruitment at two locations, and a later decline at a third location, followed by a recruitment‐driven rebound after the cyclone. Generalized environmental effects of siltation and the cyclone were also reflected in substantial changes in algal cover. Long‐term variations in environmental conditions probably cause high temporal variation over large spatial scales through effects on the survival of larvae or recruits. Localized short‐term field monitoring of such species would give a misleading picture of key factors affecting population dynamics.     

Shifting Distributions of Adult Atlantic Sturgeon Amidst Post-Industrialization and Future Impacts in the Delaware River: a Maximum Entropy Approach

Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) experienced severe declines due to habitat destruction and overfishing beginning in the late 19^th 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 19^th 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.