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.     

The effects of date of planting on field establishment of serotinous cape Proteaceae

Season of fire have marked effects on the germination and establishment of serotinous shrubs of the family Proteaceae in fynbos vegetation. To investigate reasons for this, we simulated the effects of different fire seasons by planting seeds into cleared fynbos and then followed their progress. Four species of Proteaceae were planted monthly at four sites over two and a half years. Exclosures were used to exclude rodent seed predators. Germination was confined largely to the three winter months (June–Aug.). Seeds planted from January–June had higher germination than those planted in the second half of the year. Higher levels of regeneration noted after fires in the first half of the year, were previously hypothesised to be results of predation. However, we obtained similar results despite the exclusion of seed predators. Monthly minimum temperature was strongly correlated with germination percentage but monthly rainfall was not. Loss of seed viability may be important, in determining post-fire seedling densities. Differential seedling mortality of earlier and late germinants appears to be unimportant in determining establishment levels. Our results nevertheless support the current practice of restricting management fires in fynbos to the summer-autumn period.     

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.     

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.     

A defect in mobilization of cholesteryl esters in rabbit macrophages

Macrophages provide an important way for cholesteryl esters to accumulate in tissues in pathologic amounts. We studied cholesteryl ester metabolism in thioglycollate-induced peritoneal macrophages obtained from normocholesterolemic and hypercholesterolemic rabbits. The macrophage preparations from normocholesterolemic rabbit (MN cells) had 26 nmol esterified cholesterol/mg cellular protein, incorporated 1 nmol of labeled oleate into cholesteryloleate/2 h per mg cellular protein and had an acyl-coenzyme A:cholesterol acyltransferase activity of 22 pmol cholesterylpalmitate formed/min per mg protein in isolated membranes. The macrophage preparations from hypercholesterolemic rabbits (MHC cells) contained a 12-fold greater mass of cholesteryl ester, had an 8-times higher rate of formation of cholesteryloleate, and had 3-times more acyl-coenzyme A:cholesterol acyltransferase activity in the isolated membranes. When a cholesterol acceptor (10% fetal bovine serum or 10 mg of lipid-free fetal bovine serum protein) was added to the culture medium of rabbit MHC cells, the MHC cells retained more than 70% of their cholesteryl esters after 48 h of incubation. In contrast, when a cholesterol acceptor (10% fetal bovine serum) was added to the medium of thioglycollate-induced, cholesterol-enriched macrophages from mice, the mice macrophages retained only 19% of their cholesteryl esters after 48 h of incubation. The limited capacity of rabbit macrophages to release unesterified cholesterol from stored cytoplasmic cholesteryl esters to an exogenous acceptor may be related to the propensity of rabbits to develop atherosclerotic lesions.     

Racial and other characteristics of human T cell leukemia/lymphoma (HTLV-I) and AIDS (HTLV-III) in Trinidad.

Adult T cell leukaemia/lymphoma was first recognised as a clinical entity in southwest Japan. Subsequently the Caribbean has been found to be another area where the disease is endemic, and sporadic cases have been identified in different parts of the world. The human T cell leukaemia/lymphoma virus (HTLV-I) is causally related to adult T cell leukaemia/lymphoma. A subgroup of HTLV, designated HTLV-III, has recently been isolated from many patients with the acquired immunodeficiency syndrome (AIDS) and preAIDS, and there is now evidence that this variant is the primary cause of AIDS. This is the first report from Trinidad to describe 12 cases of adult T cell leukaemia/lymphoma and 14 of AIDS. All were in patients of African descent. No cases were seen in subjects of East Indian descent, who, like those of African descent, comprise as much as 40% of the population. West Indians of African descent may have increased susceptibility to infection with both HTLV-I and HTLV-III.     

The effect of 3-sulphation and taurine conjugation on the uptake of chenodeoxycholic acid by rat hepatocytes

The hepatic uptake of chenodeoxycholic acid, taurochenodeoxycholic acid, chenodeoxycholic acid 3-sulphate and taurochenodeoxycholate acid 3-sulphate by isolated rat hepatocytes was examined. Taurochenodeoxycholic acid, taurochenodeoxycholic acid 3-sulphate and chenodeoxycholic acid 3-sulphate uptake occurred by a saturable, energy-dependent process while chenodeoxycholic acid uptake was predominantly non-saturable, possibly simple diffusion. Apparent Km (mumol/l) and Vmax (nmol/mg protein per min) values (mean +/- S.D.), respectively, were: chenodeoxycholic acid (saturable component), 33 +/- 6.4 and 4.8 +/- 0.6; taurochenodeoxycholic acid, 11.1 +/- 2.0 and 3.1 +/- 0.5; chenodeoxycholic acid 3-sulphate, 6.1 +/- 0.9 and 2.3 +/- 0.4; and taurochenodeoxycholic acid 3-sulphate, 5.0 +/- 0.7 and 0.9 +/- 0.15. Both conjugation with taurine and sulphation at the 3 position resulted in a reduction in the values of Km and Vmax. Uptake of each of the bile acids taurochenodeoxycholic acid, taurochenodeoxycholic acid 3-sulphate and chenodeoxycholic acid 3-sulphate was competitively inhibited by the other two, with taurochenodeoxycholic acid a potent inhibitor of both taurochenodeoxycholic acid 3-sulphate and chenodeoxycholic acid 3-sulphate uptake. Other bile acids also inhibited. Uptake was inhibited by albumin in the order chenodeoxycholic acid 3-sulphate greater than taurochenodeoxycholic acid 3-sulphate greater than taurochenodeoxycholic acid and was dependent on the extent of bile acid binding to albumin.