Spin Reduction Transition in Spin-3/2 Random Heisenberg Chains

Random spin-3/2 antiferromagnetic Heisenberg chains are investigated using an asymptotically exact renormalization group. Randomness is found to induce a quantum phase transition between two random-singlet phases. In the strong randomness phase the effective spins at low energies are S_eff=3/2, while in the weak randomness phase the effective spins are S_eff=1/2. Separating them is a quantum critical point near which there is a non-trivial mixture of S=1/2, S=1, and S=3/2 effective spins at low temperatures.Comment: 4 pages, 3 figures. Typos correcte

Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme

sorLA is a recently identified neuronal receptor for amyloid precursor protein (APP) that is known to interact with APP and affect its intracellular transport and processing. Decreased levels of sorLA in the brain of Alzheimer's disease (AD) patients and elevated levels of amyloid-beta peptide (Abeta) in sorLA-deficient mice point to the importance of the receptor in this neurodegenerative disorder. We analyzed APP cleavage in an APP-shedding assay and found that both sorLA and, surprisingly, a sorLA tail construct inhibited APP cleavage in a beta-site APP-cleaving enzyme (BACE)-dependent manner. In line with this finding, sorLA and the sorLA tail significantly reduced secreted Abeta levels when BACE was overexpressed, suggesting that sorLA influences beta-cleavage. To understand the effect of sorLA on APP cleavage by BACE, we analyzed whether sorLA interacts with APP and/or BACE. Because both full-length sorLA and sorLA C-terminal tail constructs were functionally relevant for APP processing, we analyzed sorLA-APP for a potential cytoplasmatic interaction domain. sorLA and C99 coimmunoprecipitated, pointing toward the existence of a new cytoplasmatic interaction site between sorLA and APP. Moreover, sorLA and BACE also coimmunoprecipitate. Thus, sorLA interacts both with BACE and APP and might therefore directly affect BACE-APP complex formation. To test whether sorLA impacts BACE-APP interactions, we used a fluorescence resonance energy transfer assay to evaluate BACE-APP interactions in cells. We discovered that sorLA significantly reduced BACE-APP interactions in Golgi. We postulate that sorLA acts as a trafficking receptor that prevents BACE-APP interactions and hence BACE cleavage of APP

Different tau species lead to heterogeneous tau pathology propagation and misfolding.

Tauopathies are a heterogeneous group of pathologies characterized by tau aggregation inside neurons. Most of them are sporadic but certain tauopathies rely on tau gene (MAPT) mutations. They particularly differ from one to another by their different neuropathological signatures e.g. lesion shapes, regions affected and molecular composition of aggregates. Six isoforms of tau exist, but they do not all co-aggregate in each tauopathy but rather have a unique signature for each one. In some tauopathies such as Alzheimer's disease (AD), tau protein aggregation follows stereotypical anatomical stages. Recent data suggest that this progression is due to an active process of tau protein propagation from neuron-to-neuron. We wondered how tau isoforms or mutations could influence the process of tau aggregation and tau propagation. In human neuropathological material, we found that MAPT mutations induce a faster misfolding compared to tau found in sporadic AD patients. In the rat brain, we observed cell-to-cell transfer of non-pathological tau species irrespective of the tested isoform or presence of a mutation. By contrast, we found that the species of tau impact the propagation of tau pathology markers such as hyperphosphorylation and misfolding. Indeed, misfolding and hyperphosphorylated tau proteins do not spread at the same rate when tau is mutated, or the isoform composition is modified. These results clearly argue for the existence of specific folding properties of tau depending on isoforms or mutations impacting the behavior of pathological tau species

A cross-institutional analysis of the effects of broadening trainee professional development on research productivity

PhD-trained scientists are essential contributors to the workforce in diverse employment sectors that include academia, industry, government, and nonprofit organizations. Hence, best practices for training the future biomedical workforce are of national concern. Complementing coursework and laboratory research training, many institutions now offer professional training that enables career exploration and develops a broad set of skills critical to various career paths. The National Institutes of Health (NIH) funded academic institutions to design innovative programming to enable this professional development through a mechanism known as Broadening Experiences in Scientific Training (BEST). Programming at the NIH BEST awardee institutions included career panels, skill-building workshops, job search workshops, site visits, and internships. Because doctoral training is lengthy and requires focused attention on dissertation research, an initial concern was that students participating in additional complementary training activities might exhibit an increased time to degree or diminished research productivity. Metrics were analyzed from 10 NIH BEST awardee institutions to address this concern, using time to degree and publication records as measures of efficiency and productivity. Comparing doctoral students who participated to those who did not, results revealed that across these diverse academic institutions, there were no differences in time to degree or manuscript output. Our findings support the policy that doctoral students should participate in career and professional development opportunities that are intended to prepare them for a variety of diverse and important careers in the workforce

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Anticholinesterase and Antioxidant Activities of Spilanthes filicaulis Whole Plant Extracts for the Management of Alzheimer’s Disease

Background: Spilanthes filicaulis is a tropical herb implicated as a memory enhancer in ethnomedicine. Objective: The study investigated acetyl/butyryl cholinesterase inhibitory and antioxidant activities of different extracts of S. filicaulis whole plant and correlated them to its phytochemical constituents. Methods: The powdered whole plant was successively extracted with n-hexane, ethyl acetate and methanol. Acetyl cholinesterase (AChE) and Butyryl cholinesterase (BuChE) inhibitory activity were evaluated by Ellman colorimetry assay. Antioxidant activity was tested using 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, ferric reducing power and nitric oxide scavenging assays. Total phenolic, flavonoid and tannin were estimated using standard methods. Correlation was determined using Quest Graph™ Regression Calculator. Results: Various extracts exhibited concentration-dependent AChE and BuChE inhibitory activity with ethyl acetate extract being the highest with IC50 of 0.77 μg/mL and 0.92 μg/mL for AChE and BuChE respectively. The ethyl acetate extract also showed the highest reducing power when compared with the other extracts. The methanol extract had slightly higher phenolic and flavonoid content and showed the highest DPPH radical scavenging effect. DPPH scavenging, AChE and BuChE inhibition had high correlation with the total flavonoid content with R2 values of 1.00, 0.800 and 0.992 respectively while nitric oxide scavenging had high correlation with phenolics and tannins with R2 = 0.942 and 0.806 respectively. Conclusion: These results show that the extracts of the whole plant of S. filicaulis possess significant AChE/BuChE inhibitory and antioxidant properties, mostly due to its flavonoid content, suggesting the possible use of the plant in neurodegenerative diseases such as AD

Soluble forms of tau are toxic in Alzheimer's disease

Accumulation of neurofibrillary tangles (NFT), intracellular inclusions of fibrillar forms of tau, is a hallmark of Alzheimer Disease. NFT have been considered causative of neuronal death, however, recent evidence challenges this idea. Other species of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now being implicated as toxic. Here we review the data supporting soluble tau as toxic to neurons and synapses in the brain and the implications of these data for development of therapeutic strategies for Alzheimer’s disease and other tauopathies

Prevalence of the dog nematode <i>Spirocerca lupi</i> in populations of its intermediate dung beetle host in the Tshwane (Pretoria) Metropole, South Africa

Spirocerca lupi (Spirurida: Spirocercidae) is a cosmopolitan parasite, principally of domestic dogs and dung beetles are its main intermediate hosts. In South Africa there has recently been growing concern over the upsurge of reported cases of clinical spirocercosis in dogs, while little is known or understood about the dynamics of the host-parasite associations between dung beetles and this nematode. We determined and compared the prevalence of infection in dung beetles between rural, urban and periurban areas of Tshwane (Pretoria) Metropole. Dung beetles were sampled during April and October 2006, at various localities in each of these areas. Localities were selected on the basis of being focal areas of high infection with S. lupi in dogs. Pig, dog and cow dung-baited pitfall traps were used for sampling the beetles. Trap contents were collected 48 h after the traps had been set and only dung beetles were collected from the traps. In total, 453 specimens belonging to 18 species were collected from 63 pitfall traps in all three areas. The numbers of species that were collected varied among the three areas. Dung beetles, irrespective of species (18) and numbers (447), predominantly preferred pig dung. The prevalence of dung beetles infected with the larvae of S. lupi varied considerably in the three areas. In the urban area 13.5 % of the dung beetles dissected were infected, while the prevalence of S. lupi in dung beetles in the rural area was 2.3 %. All the dung beetles that were infected with this nematode showed a preference for omnivore (pig and dog) dung