Cell biological mechanisms of activity-dependent synapse to nucleus translocation of CRTC1 in neurons.

Previous studies have revealed a critical role for CREB-regulated transcriptional coactivator (CRTC1) in regulating neuronal gene expression during learning and memory. CRTC1 localizes to synapses but undergoes activity-dependent nuclear translocation to regulate the transcription of CREB target genes. Here we investigate the long-distance retrograde transport of CRTC1 in hippocampal neurons. We show that local elevations in calcium, triggered by activation of glutamate receptors and L-type voltage-gated calcium channels, initiate active, dynein-mediated retrograde transport of CRTC1 along microtubules. We identify a nuclear localization signal within CRTC1, and characterize three conserved serine residues whose dephosphorylation is required for nuclear import. Domain analysis reveals that the amino-terminal third of CRTC1 contains all of the signals required for regulated nucleocytoplasmic trafficking. We fuse this region to Dendra2 to generate a reporter construct and perform live-cell imaging coupled with local uncaging of glutamate and photoconversion to characterize the dynamics of stimulus-induced retrograde transport and nuclear accumulation

Mean reversion and convergence of ecological footprint in the MENA region: evidence from a fractional integration procedure.

This paper deals with the analysis of mean reversion and convergence of the ecological footprint (EF) in the MENA region. Using a long memory model based on fractional integration, we find that the results are very heterogeneous across countries depending on the assumptions made on the error term and the use of original versus logged data. Nevertheless, some conclusions can be obtained. Thus, mean reversion is decisively found in the case of Tunisia, and other countries showing some degree of reversion to the mean include Israel, Syria, Yemen, and Iran. Dealing with the issue of convergence within the MENA countries, similar conclusions hold and only Tunisia reports statistical evidence of convergence for the two types of errors. Additional evidence is found in the case of Syria, Yemen, and Jordania with uncorrelated errors and for Iran with autocorrelation. It is recommended that environmental policies targeted at stabilizing the trends in EF in the MENA region should not be indiscriminately applied in consideration of the heterogeneous nature of the series in the regionpost-print728 K

BradPhys to BradViz or from archaeological science to heritage science

YesArchaeology is a broad church and its role as a “two culture” discipline is frequently cited. This position at the interface of the arts and sciences remains central to archaeological activity but there have been significant changes in the structure of archaeology and its relationship to society overall. The growth of heritage science, in particular, is driving change and development within archaeology at a national and international level. This paper discusses these developments in relation to the author's own research trajectory and discusses the significance of such change

Validation of a chloroquine-induced cell death mechanism for clinical use against malaria

An alternative antimalarial pathway of an ‘outdated’ drug, chloroquine (CQ), may facilitate its return to the shrinking list of effective antimalarials. Conventionally, CQ is believed to interfere with hemozoin formation at nanomolar concentrations, but resistant parasites are able to efflux this drug from the digestive vacuole (DV). However, we show that the DV membrane of both resistant and sensitive laboratory and field parasites is compromised after exposure to micromolar concentrations of CQ, leading to an extrusion of DV proteases. Furthermore, only a short period of exposure is required to compromise the viability of late-stage parasites. To study the feasibility of this strategy, mice malaria models were used to demonstrate that high doses of CQ also triggered DV permeabilization in vivo and reduced reinvasion efficiency. We suggest that a time-release oral formulation of CQ may sustain elevated blood CQ levels sufficiently to clear even CQ-resistant parasites

Outlier-robust manifold pre-integration for INS/GPS fusion

We tackle the INS/GPS sensor fusion problem for pose estimation, particularly in the common setting where the INS components (IMU and magnetometer) function at much higher frequencies than GPS, and where the magnetometer and GPS are prone to giving erroneous measurements (outliers) due to magnetic disturbances and glitches. Our main contribution is a novel non-linear optimization framework that (1) fuses preintegrated IMU and magnetometer measurements with GPS, in a manner that respects the manifold structure of the state space; and (2) supports the usage of robust norms and efficient large scale optimization to effectively mitigate the effects of outliers. Through extensive experiments, we demonstrate the superior accuracy and robustness of our approach over filtering methods (which are customarily applied in the target setting) with minimal impact to computational efficiency. Our work further illustrates the strength of optimization approaches in state estimation problems and paves the way for their adoption in the control and navigation communities.Shin-Fang Ch'ng, Alireza Khosravian, Anh-Dzung Doan and Tat-Jun Chi

A whole cell pathway screen reveals seven novel chemosensitizers to combat chloroquine resistant malaria

Due to the widespread prevalence of resistant parasites, chloroquine (CQ) was removed from front-line antimalarial chemotherapy in the 1990s despite its initial promise of disease eradication. Since then, resistance-conferring mutations have been identified in transporters such as the PfCRT, that allow for the efflux of CQ from its primary site of action, the parasite digestive vacuole. Chemosensitizing/ chemoreversing compounds interfere with the function of these transporters thereby sensitizing parasites to CQ once again. However, compounds identified thus far have disappointing in vivo efficacy and screening for alternative candidates is required to revive this strategy. In this study, we propose a simple and direct means to rapidly screen for such compounds using a fluorescent-tagged CQ molecule. When this screen was applied to a small library, seven novel chemosensitizers (octoclothepin, methiothepin, metergoline, loperamide, chlorprothixene, L-703,606 and mibefradil) were quickly elucidated, including two which showed greater potency than the classical chemosensitizers verapamil and desipramine

Cityscapes without figures: geophysics, computing and the future of urban studies

Ye

Mediation analysis of conspiratorial thinking and anti-expert sentiments on vaccine willingness

Objective: Vaccines are an effective means to reduce the spread of diseases, but they are sometimes met with hesitancy that needs to be understood. Method: In this study, we analyzed data from a large, cross-country survey conducted between June and August 2021 in 43 countries (N = 15,740) to investigate the roles of trust in government and science in shaping vaccine attitudes and willingness to be vaccinated. Results: Despite significant variability between countries, we found that both forms of institutional trust were associated with a higher willingness to receive a COVID-19 vaccine. Furthermore, we found that conspiratorial thinking and anti-expert sentiments predicted reduced trust in government and science, respectively, and that trust mediated the relationship between these two constructs and ultimate vaccine attitudes. Although most countries displayed similar relationships between conspiratorial thinking and anti-expert sentiments, trust in government and science, and vaccine attitudes, we identified three countries (Brazil, Honduras, and Russia) that demonstrated significantly altered associations between the examined variables in terms of significant random slopes. Conclusions: Cross-country differences suggest that local governments’ support for COVID-19 prevention policies can influence populations’ vaccine attitudes. These findings provide insight for policymakers to develop interventions aiming to increase trust in the institutions involved in the vaccination process