Clathrin adaptor AP-1–mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments

One of the hallmarks of Alzheimer’s disease is the accumulation of toxic amyloid-β (Aβ) peptides in extracellular plaques. The direct precursor of Aβ is the carboxyl-terminal fragment β (or C99) of the amyloid precursor protein (APP). C99 is detected at elevated levels in Alzheimer’s disease brains, and its intracellular accumulation has been linked to early neurotoxicity independently of Aβ. Despite this, the causes of increased C99 levels are poorly understood. Here, we demonstrate that APP interacts with the clathrin vesicle adaptor AP-1 (adaptor protein 1), and we map the interaction sites on both proteins. Using quantitative kinetic trafficking assays, established cell lines and primary neurons, we also show that this interaction is required for the transport of APP from the trans-Golgi network to endosomes. In addition, disrupting AP-1-mediated transport of APP alters APP processing and degradation, ultimately leading to increased C99 production and Aβ release. Our results indicate that AP-1 regulates the subcellular distribution of APP, altering its processing into neurotoxic fragments.     

Biomass production and carbon dioxide fixation by Aphanothece microscopica Nägeli in a bubble column photobioreactor

The objective of the present study was to evaluate the growth kinetics of Aphanothece microscopica Nägeli under different conditions of temperature, light intensity and CO₂ concentration. The growth kinetics of the microorganism and carbon biofixation were evaluated using a central composite design, considering five different temperature levels (21.5, 25, 30, 35 and 38.5 °C), light intensities (0.96, 3, 6, 9 and 11 klux) and carbon dioxide concentrations (3, 15, 25, 50 and 62%). The results obtained showed the effects of temperature, light intensity and CO₂ concentration (p < 0.05) on the photosynthetic metabolism of the microorganism. Response surface methodology was adequate for process optimisation, providing a carbon fixation rate to the order of 109.2 mg L⁻¹ h⁻¹ under conditions of 11 klux, 35 °C and 15% carbon dioxide, representing an increase of 58.1% as compared to the conditions tested initially.     

A new method to infer vegetation boundary movement from ‘snapshot’ data

Global change may induce shifts in plant community distributions at multiple spatial scales. At the ecosystem scale, such shifts may result in movement of ecotones or vegetation boundaries. Most indicators for ecosystem change require timeseries data, but here a new method is proposed enabling inference of vegetation boundary movement from one ‘snapshot’ (e.g. an aerial photograph or satellite image) in time. The method compares the average spatial position of frontrunners of both communities along the vegetation boundary. Mathematical analyses and simulation modeling show that the average frontrunner position of retreating communities is always farther away from a so‐called optimal vegetation boundary as compared to that of the expanding community. This feature does not depend on assumptions about plant dispersal or competition characteristics. The method is tested with snapshot data of a northern hardwood‐boreal forest mountain ecotone in Vermont, a forest‐mire ecotone in New Zealand and a subalpine treeline‐tundra ecotone in Montana. The direction of vegetation boundary movement is accurately predicted for these case studies, but we also discuss potential caveats. With the availability of snapshot data rapidly increasing, the method may provide an easy tool to assess vegetation boundary movement and hence ecosystem responses to changing environmental conditions.     

1,2,4]Triazole derivatives as 5-HT(1A) serotonin receptor ligands.

A series of new 4-amino-3-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl] propyl]thio]-5-(substitutedphenyl)[1,2,4]triazoles 11a-t was synthesized in order to obtain compounds with high affinity and selectivity for 5-HT(1A) receptor over the alpha(1)-adrenoceptor. A series of isomeric 4-amino-2-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl]propyl]-5-(substitutedphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r was also isolated and characterized. New compounds were tested to evaluate their affinity for 5-HT(1A) receptor and alpha(1)-adrenoceptor in radioligand binding experiments. As a general trend, triazoles 11a-t showed a preferential affinity for the 5-HT(1A) receptor whereas isomeric 2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r preferentially bind to the alpha(1)-adrenoceptor site. Several molecules showed affinities in the nanomolar range and 4-amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(4-propyloxy-phenyl)[1,2,4]triazole (11o) was the most selective derivative for the 5-HT(1A) receptor (K(i) alpha(1)/K(i) 5-HT(1A)=55). The decrease in 5-HT(1A) receptor selectivity in 3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(substitutedphenyl)[1,2,4] triazole 14a-b, lacking in the amino group in 4-position of the triazole ring, in comparison with their analogues in the series 11a-t, suggest that the amino function represents a critical structural feature in determining 5-HT(1A) receptor selectivity in this class of compounds.     

Substitute running outputs in elite youth male soccer players: less peak but greater relative running outputs

Coaches consider substitute players to be a substantial factor in influencing the outcome of a soccer match. Substitute players are expected to make physical impact on the match by superseding the running output of the player they replaced and are a key tool for managing in-game fatigue and influencing the outcome of a game. This study investigated the physical impact and internal response of substitute players, compared to starting and full-match players. We also sought to determine if differences between substitution statuses were influenced by playing position. Players wore 15-Hz global positioning system tracking devices across 29 competition matches and were categorised according to their substitution status (full-match, starters, substitutes) and playing position (external defender, midfield, external attacker and central attacker). Peak total (TD) and high-speed running (> 5.0 m/s) distance (HSRD) were calculated using 1-, 2- and 5-minute rolling epochs. Relative running demands were reported as TD and HSRD per minute of total playing time. Substitute players performed less peak TD and HSRD in 1-, 2- and 5-minute epochs, and reported lower RPE compared to starting and full-match players. In contrast, substitutes performed greater relative HSRD per minute than starting and full-match players (p < 0.001, |d| range = 0.35–1.34). In conclusion, substitute players may have a relative physical impact but do not replicate or supersede the peak demands of full-match players. Coaches and practitioners should implement targeted warm-up interventions to enhance substitute readiness to meet the peak running demands in order to have a more effective physical impact.     

Corrigendum

Meiotic chromosome segregation requires pairwise association between homologs, stabilized by the synaptonemal complex (SC). Here, we investigate factors contributing to pairwise synapsis by investigating meiosis in polyploid worms. We devised a strategy, based on transient inhibition of cohesin function, to generate polyploid derivatives of virtually any Caenorhabditis elegans strain. We exploited this strategy to investigate the contribution of recombination to pairwise synapsis in tetraploid and triploid worms. In otherwise wild-type polyploids, chromosomes first sort into homolog groups, then multipartner interactions mature into exclusive pairwise associations. Pairwise synapsis associations still form in recombination-deficient tetraploids, confirming a propensity for synapsis to occur in a strictly pairwise manner. However, the transition from multipartner to pairwise association was perturbed in recombination-deficient triploids, implying a role for recombination in promoting this transition when three partners compete for synapsis. To evaluate the basis of synapsis partner preference, we generated polyploid worms heterozygous for normal sequence and rearranged chromosomes sharing the same pairing center (PC). Tetraploid worms had no detectable preference for identical partners, indicating that PC-adjacent homology drives partner choice in this context. In contrast, triploid worms exhibited a clear preference for identical partners, indicating that homology outside the PC region can influence partner choice. Together, our findings, suggest a two-phase model for C. elegans synapsis: an early phase, in which initial synapsis interactions are driven primarily by recombination-independent assessment of homology near PCs and by a propensity for pairwise SC assembly, and a later phase in which mature synaptic interactions are promoted by recombination.     

Variation in morphological and chemical traits of Mediterranean tree roots: linkage with leaf traits and soil conditions

Plant and Soil - Na+/H+ antiporter (NHX1) was reported to be induced by NaCl in plants and NaCl can alleviate the toxic effect in plants caused by cadmium (Cd). However, it is unknown whether the...     

Integrating multi-scale data on homologous recombination into a new recognition mechanism based on simulations of the RecA-ssDNA/dsDNA structure

RecA protein is the prototypical recombinase. Members of the recombinase family can accurately repair double strand breaks in DNA. They also provide crucial links between pairs of sister chromatids in eukaryotic meiosis. A very broad outline of how these proteins align homologous sequences and promote DNA strand exchange has long been known, as are the crystal structures of the RecA-DNA pre- and postsynaptic complexes; however, little is known about the homology searching conformations and the details of how DNA in bacterial genomes is rapidly searched until homologous alignment is achieved. By integrating a physical model of recognition to new modeling work based on docking exploration and molecular dynamics simulation, we present a detailed structure/function model of homology recognition that reconciles extremely quick searching with the efficient and stringent formation of stable strand exchange products and which is consistent with a vast body of previously unexplained experimental results.