The cyclin-dependent kinase 5 activators p35 and p39 interact with the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II and alpha-actinin-1 in a calcium-dependent manner

Cyclin-dependent kinase 5 (Cdk5) is a critical regulator of neuronal migration in the developing CNS, and recent studies have revealed a role for Cdk5 in synaptogenesis and regulation of synaptic transmission. Deregulation of Cdk5 has been linked to the pathology of neurodegenerative diseases such as Alzheimer\u27s disease. Activation of Cdk5 requires its association with a regulatory subunit, and two Cdk5 activators, p35 and p39, have been identified. To gain further insight into the functions of Cdk5, we identified proteins that interact with p39 in a yeast two-hybrid screen. In this study we report that alpha-actinin-1 and the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II (CaMKIIalpha), two proteins localized at the postsynaptic density, interact with Cdk5 via their association with p35 and p39. CaMKIIalpha and alpha-actinin-1 bind to distinct regions of p35 and p39 and also can interact with each other. The association of CaMKIIalpha and alpha-actinin-1 to the Cdk5 activators, as well as to each other, is stimulated by calcium. Further, the activation of glutamate receptors increases the association of p35 and p39 with CaMKIIalpha, and the inhibition of CaMKII activation diminishes this effect. The glutamate-mediated increase in association of p35 and CaMKIIalpha is mediated in large part by NMDA receptors, suggesting that cross talk between the Cdk5 and CaMKII signal transduction pathways may be a component of the complex molecular mechanisms contributing to synaptic plasticity, memory, and learning

Unfair play? Video games as exploitative monetized services: An examination of game patents from a consumer protection perspective

Video games as a consumer product have changed significantly with the advent of in-game purchasing systems (e.g., microtransactions, ‘loot boxes’). This review examines consumer protections related to in-game purchasing by anticipating some of the potential design strategies that might contribute to higher risk consumer behavior. Attention was directed towards the analysis of patents for potential in-game purchasing systems, with 13 identified on Google Patents. The design features were analysed in relation to the consumer rights and guarantees described in the terms of use agreements of the patent assignees. The analysis revealed that some in-game purchasing systems could be characterized as unfair or exploitative. These systems describe tactics that capitalize on informational advantages (e.g., behavioral tracking) and data manipulation (e.g., price manipulation) to optimize offers to incentivize continuous spending, while offering limited or no guarantees or protections (e.g., refund entitlement), with the potential to exploit vulnerable players (e.g., adolescents, problematic gamers). These findings are critically discussed in relation to behavioral economics, addiction psychology, and the clinical conceptualization of gaming disorder. Appropriate policy and consumer protection measures, psychologically informed interventions, and ethical game design guidelines are needed in order to protect the interests and wellbeing of consumers

Factors affecting the recovery of Mexican wolves in the Southwest United States

Recovering and maintaining large carnivore populations is a global conservation challenge that requires better knowledge of the factors affecting their populations, particularly in shared landscapes (i.e. non-protected areas where people occupy and or utilize the land). The Mexican wolf (Canis lupus baileyi) is an endangered wolf subspecies being recovered on shared landscapes in the Southwest United States and Mexico. We used data from the U.S. program to model population growth, evaluate the impact of management removal and illegal killing relative to other demographic factors, and test hypotheses about factors influencing rates of management removal and illegal killing. From 1998 to 2019, the population growth averaged 12% per year. Rates of natural reproduction, illegal killing and other mortality remained consistent over the 22 years; while releases, translocations and management removals varied markedly between two time periods, phase 1:1998–2007 and phase 2:2008–2019. The number of wolves removed for conflict management was higher during phase 1 (average ~ 13 per year, rate = 24.8%) than phase 2 (average of ~5 per year, rate = 5.2%). This decrease in management removal resulted in the wolf population resuming growth after a period of population stagnation. Two factors influenced this decrease, a change in policy regarding removal of wolves (stronger modelling support) and a decrease in the number of captive-reared adult wolves released into the wild (weaker modelling support). Illegal mortality was relatively constant across both phases, but after the decrease in management removal, illegal mortality became the most important factor (relative importance shifted from 28.2% to 50.1%). Illegal mortality was positively correlated with rates of reintroduction and translocation of wolves and negatively correlated with the rate of management removal. 6. Synthesis and applications. Using management removal to reduce human–carnivore conflict can have negative population impacts if not used judiciously. Recovering and maintaining carnivore populations in shared landscapes may require greater tolerance of conflict and more emphasis on effective conflict prevention strategies and compensation programs for affected stakeholders

A new negative control gene for amino acid biosynthesis in Saccharomyces cerevisiae

Enzyme levels in multiple amino acid biosynthetic pathways in yeast are coregulated. This control is effected largely at the transcriptional level by a number. of regulatory genes. We report the isolation and characterization of a new negative regulatory gene, GCD4 , for this general control system. GCD4 mutations are recessive and define a single Mendelian gene on chromosome 111. A gcd4 mutation results in resistance to different amino acid analogs and elevated, but fully inducible, mRNA levels of genes under general control. Epistasis analysis indicates that GCD4 acts more directly than the positive regulators GCN1, GCN2, GCN3 and GCN5 , but less directly than GCN4 , on the transcription of the amino acid biosynthetic genes. These data imply that GCD4 is a negative regulator of the positive effector, GCN4 . Although GCD4 occupies the same position relative to the GCN genes as other GCD genes, it produces a unique phenotype. These results illustrate the diversity of function of negative regulators in general control.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46958/1/294_2004_Article_BF00447382.pd

Eph-Dependent Tyrosine Phosphorylation of Ephexin1 Modulates Growth Cone Collapse

SummaryEphs regulate growth cone repulsion, a process controlled by the actin cytoskeleton. The guanine nucleotide exchange factor (GEF) ephexin1 interacts with EphA4 and has been suggested to mediate the effect of EphA on the activity of Rho GTPases, key regulators of the cytoskeleton and axon guidance. Using cultured ephexin1−/− mouse neurons and RNA interference in the chick, we report that ephexin1 is required for normal axon outgrowth and ephrin-dependent axon repulsion. Ephexin1 becomes tyrosine phosphorylated in response to EphA signaling in neurons, and this phosphorylation event is required for growth cone collapse. Tyrosine phosphorylation of ephexin1 enhances ephexin1’s GEF activity toward RhoA while not altering its activity toward Rac1 or Cdc42, thus changing the balance of GTPase activities. These findings reveal that ephexin1 plays a role in axon guidance and is regulated by a switch mechanism that is specifically tailored to control Eph-mediated growth cone collapse

Detection of intrinsic source structure at ~3 Schwarzschild radii with Millimeter-VLBI observations of SAGITTARIUS A*

We report results from very long baseline interferometric (VLBI) observations of the supermassive black hole in the Galactic center, Sgr A*, at 1.3 mm (230 GHz). The observations were performed in 2013 March using six VLBI stations in Hawaii, California, Arizona, and Chile. Compared to earlier observations, the addition of the APEX telescope in Chile almost doubles the longest baseline length in the array, provides additional {\it uv} coverage in the N-S direction, and leads to a spatial resolution of $\sim$30 $\mu$as ($\sim$3 Schwarzschild radii) for Sgr A*. The source is detected even at the longest baselines with visibility amplitudes of $\sim$4-13% of the total flux density. We argue that such flux densities cannot result from interstellar refractive scattering alone, but indicate the presence of compact intrinsic source structure on scales of $\sim$3 Schwarzschild radii. The measured nonzero closure phases rule out point-symmetric emission. We discuss our results in the context of simple geometric models that capture the basic characteristics and brightness distributions of disk- and jet-dominated models and show that both can reproduce the observed data. Common to these models are the brightness asymmetry, the orientation, and characteristic sizes, which are comparable to the expected size of the black hole shadow. Future 1.3 mm VLBI observations with an expanded array and better sensitivity will allow a more detailed imaging of the horizon-scale structure and bear the potential for a deep insight into the physical processes at the black hole boundary.Comment: 11 pages, 5 figures, accepted to Ap

STA-20 : an ABC-6 zeotype structure prepared by co-templating and solved via a hypothetical structure database and STEM-ADF imaging

This work has been supported by Johnson Matthey PLC, UK. AEW acknowledges funding from an EPSRC/Johnson Matthey Industrial CASE PhD award EP/N50936X/1. We acknowledge Diamond Light Source for time on beamline I11 under the funded Proposal EE11830-1.A microporous silicoaluminophosphate with a novel topology type, STA-20, has been prepared via a dual templating method using hexamethylene bisdiazabicyclooctane (diDABCO-C6) and trimethylamine as co-templates. Its structure has been solved and confirmed using a multi-technique approach that included the use of a hypothetical zeolite database to obtain a candidate starting structure, followed by scanning transmission electron microscopy with annular dark field imaging and Rietveld refinement. STA-20 is a member of the ABC-6 family of zeotype structures. The structure has trigonal symmetry, P-31c, with a = 13.15497(18) Å and c = 30.5833(4) Å in the calcined form. It has a 12-layer stacking sequence of 6-rings (6Rs), AABAABAACAAC(A), which contains single and double 6R units. As well as d6r, can and gme cages, STA-20 possesses the longest cage observed in an ordered ABC-6 material, giving a 3D-connected pore system limited by 8R windows. Models for the location of the templates within cages of the framework were obtained by combining elemental analysis, 13C MAS NMR, computer modelling and Rietveld refinement.PostprintPostprintPeer reviewe