Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ42 Oligomers and Protect Synapses.

Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ42) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ42 oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects vs. fibrils on synapses and protection by Aβ-phagocytic macrophages. We found that cortical neurons were more susceptible to Aβ42 oligomers than fibrils, triggering additional neuritic arborization retraction, functional alterations (hyperactivity and spike waveform), and loss of VGluT1- and PSD95-excitatory synapses. Co-culturing neurons with bone marrow-derived macrophages protected synapses against Aβ42 fibrils; moreover, immune activation with glatiramer acetate (GA) conferred further protection against oligomers. Mechanisms involved increased Aβ42 removal by macrophages, amplified by GA stimulation: fibrils were largely cleared through intracellular CD36/EEA1+-early endosomal proteolysis, while oligomers were primarily removed via extracellular/MMP-9 enzymatic degradation. In vivo studies in GA-immunized or CD115+-monocyte-grafted APPSWE/PS1ΔE9-transgenic mice followed by pre- and postsynaptic analyses of entorhinal cortex and hippocampal substructures corroborated our in vitro findings of macrophage-mediated synaptic preservation. Together, our data demonstrate that activated macrophages effectively clear Aβ42 oligomers and rescue VGluT1/PSD95 synapses, providing rationale for harnessing macrophages to treat AD

The roles of history and habitat area in the distribution and composition of avian species assemblages in the highlands of Costa Rica

Bird species assemblages in isolated Neotropical highland mountains have been moulded by the drastic climatic changes that occurred in late Pleistocene. Palynological evidence indicates that after the Pleistocene the highlands of Costa Rica and western Panama became isolated as climate turned gradually more tropical and highland vegetation retreated to the upper elevations of high mountains, forming highland islands. We surveyed birds at 10 representative sites throughout the Costa Rican highlands in order to determine the species composition of highland endemic assemblages. The area of available highland habitat explains 77% of the variance in species richness of the 36 highland endemics across highland islands, and the composition of these species assemblages have a nested distribution, rather than beingindependent sets of species on eachisland. The observed nested patternismore consistent with a differential extinction model of species assemblages, and less likely to be explained by differential migration. We conclude that the reduction of highland vegetation and the avifauna associated with it, and its subsequent confinement to the summit of high mountains, is a possible explanation for the current distribution of highland endemic species in Costa Rican highland islands.Centro Agronómico Tropical de Investigación y Enseñanza (CATIE)UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Biologí

Effect of barriers and distance on song, genetic, and morphological divergence in the highland endemic Timberline Wren (Thryorchilus browni, Troglodytidae)

Populations may become isolated by distance, geographic barriers or both. Isolated populations often diverge in behavioral, morphological and genetic traits as a result of reduced inter-population gene flow. Highland species commonly present naturally fragmented distributions that confine populations to the highest mountain peaks, isolated by mountain passes and distance. The endemic Timberline Wren (Thryorchilus browni) inhabits the highlands of the Talamanca mountain range, including western Panama, and the highest peak in the Central Volcanic mountain range of Costa Rica. Using microsatellites and song recordings we studied the effect of a geographic barrier and distance on song, genetic and morphological divergence among four populations in Costa Rica. A lowland mountain pass resulted in the largest genetic, vocal, and morphological (bill length) differences among populations, likely due to reduce the gene flow. Cultural drift and assortative mating by females selecting songs from their own population likely accentuates the effect of isolation and limited gene flow between populations. This pattern of population divergence has been found in other Neotropical highland birds, but over larger geographical scales. We conclude that mountain passes and distance both reduce gene flow between populations in recently-isolated highland species with restricted distributions.Universidad de Costa Rica/[]/UCR/Costa RicaUCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Biologí

Blooming plant species diversity patterns in two adjacent Costa Rican highland ecosystems

The Costa Rican Paramo is a unique ecosystem with high levels of endemism that is geographically isolated from the Andean Paramos. Paramo ecosystems occur above Montane Forests, below the permanent snow level, and their vegetation notably differs from that of adjacent Montane Forests. We compared the composition and beta diversity of blooming plant species using phenological data from functional plant groups (i.e., insect-visited, bird-visited and insect+bird-visited plants) between a Paramo and a Montane Forest site in Costa Rica and analyzed seasonal changes in blooming plant diversity between the rainy and dry seasons. Species richness was higher in the Montane Forest for all plant categories, except for insect- 32 visited plants, which was higher in the Paramo. Beta diversity and blooming plant composition differed between both ecosystems and seasons. Differences in species richness and beta diversity between Paramo and the adjacent Montane Forest are likely the result of dispersal events that occurred during the last glacial period and subsequent isolation, as climate turned to tropical conditions after the Pleistocene, and to stressful abiotic conditions in the Paramo ecosystem that limits species establishment. Differences in blooming plant composition between both ecosystems and seasons are likely attributed to differential effects of climatic cues triggering the flowering events in each ecosystem, but phylogenetic conservatism cannot be discarded. Analyzes of species composition and richness based on flowering phenology data are useful to evaluate potential floral resources for floral visitors (insects and birds) and how these resources change spatially and temporarily in endangered ecosystems such as the Paramo.Ministerio de Ciencia y Tecnología/[FI-040B-19]/MICIT-CONICYT/Costa RicaUCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de BiologíaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biodiversidad y Ecología Tropical (CIBET

Current status of the peach palm (Bactris gasipaes) germoplasm bank, Guapiles, Costa Rica.

The objective of this study was to determine the current status of the peach palm germoplasm bank at Los Diamantes Experimental Station (BGPLD). Lost accessions were quantified and missing passport data for the remaining accessions was obtained. The passport data was obtained from the diary created by Jorge Mora Urpí, founder of the bank, in 1972. To complete the information of accessions without data, bibliographic resources were used. In 2013, a census was conducted to determine the number of surviving palm trees. Originally, the bank was composed of 7286 palms representing 837 accessions from nine countries. A total of 1471 individuals belonging to the western group and 1271 to the eastern group were identified. Currently, only 805 individuals survive (11.1%). A lower mortality was observed in the palms from the western group (62.2 ± 41.5%) compared to those in the eastern group (81.5 ± 19.6 %). The BGPLD is in a critical condition of deterioration. Urgent and concrete institutional policies are needed to rescue this important plant genetic resourceVicerrectoría de Investigación, Universidad de Costa RicaUCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Biologí

Quantum Nonlocality without Entanglement

We exhibit an orthogonal set of product states of two three-state particles that nevertheless cannot be reliably distinguished by a pair of separated observers ignorant of which of the states has been presented to them, even if the observers are allowed any sequence of local operations and classical communication between the separate observers. It is proved that there is a finite gap between the mutual information obtainable by a joint measurement on these states and a measurement in which only local actions are permitted. This result implies the existence of separable superoperators that cannot be implemented locally. A set of states are found involving three two-state particles which also appear to be nonmeasurable locally. These and other multipartite states are classified according to the entropy and entanglement costs of preparing and measuring them by local operations.Comment: 27 pages, Latex, 6 ps figures. To be submitted to Phys. Rev. A. Version 2: 30 pages, many small revisions and extensions, author added. Version 3: Proof in Appendix D corrected, many small changes; final version for Phys. Rev. A Version 4: Report of Popescu conjecture modifie

Reproductive biology of Macleania rupestris (Ericaceae), a pollen-limited Neotropical cloud-forest species in Costa Rica

Sin abstractVicerrectoría de Investigación, Universidad de Costa Rica, MICIT-CONICYTUCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Biologí

The mechanism of H171T resistance reveals the importance of Nδ-protonated His171 for the binding of allosteric inhibitor BI-D to HIV-1 integrase

Background: Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an important new class of anti-HIV-1 agents. ALLINIs bind at the IN catalytic core domain (CCD) dimer interface occupying the principal binding pocket of its cellular cofactor LEDGF/p75. Consequently, ALLINIs inhibit HIV-1 IN interaction with LEDGF/p75 as well as promote aberrant IN multimerization. Selection of viral strains emerging under the inhibitor pressure has revealed mutations at the IN dimer interface near the inhibitor binding site. Results: We have investigated the effects of one of the most prevalent substitutions, H171T IN, selected under increasing pressure of ALLINI BI-D. Virus containing the H171T IN substitution exhibited an ~68-fold resistance to BI-D treatment in infected cells. These results correlated with ~84-fold reduced affinity for BI-D binding to recombinant H171T IN CCD protein compared to its wild type (WT) counterpart. However, the H171T IN substitution only modestly affected IN-LEDGF/p75 binding and allowed HIV-1 containing this substitution to replicate at near WT levels. The x-ray crystal structures of BI-D binding to WT and H171T IN CCD dimers coupled with binding free energy calculations revealed the importance of the Nδ- protonated imidazole group of His171 for hydrogen bonding to the BI-D tert-butoxy ether oxygen and establishing electrostatic interactions with the inhibitor carboxylic acid, whereas these interactions were compromised upon substitution to Thr171. Conclusions: Our findings reveal a distinct mechanism of resistance for the H171T IN mutation to ALLINI BI-D and indicate a previously undescribed role of the His171 side chain for binding the inhibitor. Electronic supplementary material The online version of this article (doi:10.1186/s12977-014-0100-1) contains supplementary material, which is available to authorized users

Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ₄₂ Oligomers and Protect Synapses

Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ₄₂) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ₄₂ oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects vs. fibrils on synapses and protection by Aβ-phagocytic macrophages. We found that cortical neurons were more susceptible to Aβ₄₂ oligomers than fibrils, triggering additional neuritic arborization retraction, functional alterations (hyperactivity and spike waveform), and loss of VGluT1- and PSD95-excitatory synapses. Co-culturing neurons with bone marrow-derived macrophages protected synapses against Aβ₄₂ fibrils; moreover, immune activation with glatiramer acetate (GA) conferred further protection against oligomers. Mechanisms involved increased Aβ₄₂ removal by macrophages, amplified by GA stimulation: fibrils were largely cleared through intracellular CD36/EEA1⁺-early endosomal proteolysis, while oligomers were primarily removed via extracellular/MMP-9 enzymatic degradation. In vivo studies in GA-immunized or CD115⁺-monocyte-grafted APP_(SWE)/PS1_(ΔE9)-transgenic mice followed by pre- and postsynaptic analyses of entorhinal cortex and hippocampal substructures corroborated our in vitro findings of macrophage-mediated synaptic preservation. Together, our data demonstrate that activated macrophages effectively clear Aβ₄₂ oligomers and rescue VGluT1/PSD95 synapses, providing rationale for harnessing macrophages to treat AD