Cerebellum Transcriptome of Mice Bred for High Voluntary Activity Offers Insights into Locomotor Control and Reward-Dependent Behaviors.

The role of the cerebellum in motivation and addictive behaviors is less understood than that in control and coordination of movements. High running can be a self-rewarding behavior exhibiting addictive properties. Changes in the cerebellum transcriptional networks of mice from a line selectively bred for High voluntary running (H) were profiled relative to an unselected Control (C) line. The environmental modulation of these changes was assessed both in activity environments corresponding to 7 days of Free (F) access to running wheel and to Blocked (B) access on day 7. Overall, 457 genes exhibited a significant (FDR-adjusted P-value < 0.05) genotype-by-environment interaction effect, indicating that activity genotype differences in gene expression depend on environmental access to running. Among these genes, network analysis highlighted 6 genes (Nrgn, Drd2, Rxrg, Gda, Adora2a, and Rab40b) connected by their products that displayed opposite expression patterns in the activity genotype contrast within the B and F environments. The comparison of network expression topologies suggests that selection for high voluntary running is linked to a predominant dysregulation of hub genes in the F environment that enables running whereas a dysregulation of ancillary genes is favored in the B environment that blocks running. Genes associated with locomotor regulation, signaling pathways, reward-processing, goal-focused, and reward-dependent behaviors exhibited significant genotype-by-environment interaction (e.g. Pak6, Adora2a, Drd2, and Arhgap8). Neuropeptide genes including Adcyap1, Cck, Sst, Vgf, Npy, Nts, Penk, and Tac2 and related receptor genes also exhibited significant genotype-by-environment interaction. The majority of the 183 differentially expressed genes between activity genotypes (e.g. Drd1) were under-expressed in C relative to H genotypes and were also under-expressed in B relative to F environments. Our findings indicate that the high voluntary running mouse line studied is a helpful model for understanding the molecular mechanisms in the cerebellum that influence locomotor control and reward-dependent behaviors

Parallel Adaptive Divergence among Geographically Diverse Human Populations

Few genetic differences between human populations conform to the classic model of positive selection, in which a newly arisen mutation rapidly approaches fixation in one lineage, suggesting that adaptation more commonly occurs via moderate changes in standing variation at many loci. Detecting and characterizing this type of complex selection requires integrating individually ambiguous signatures across genomically and geographically extensive data. Here, we develop a novel approach to test the hypothesis that selection has favored modest divergence at particular loci multiple times in independent human populations. We find an excess of SNPs showing non-neutral parallel divergence, enriched for genic and nonsynonymous polymorphisms in genes encompassing diverse and often disease related functions. Repeated parallel evolution in the same direction suggests common selective pressures in disparate habitats. We test our method with extensive coalescent simulations and show that it is robust to a wide range of demographic events. Our results demonstrate phylogenetically orthogonal patterns of local adaptation caused by subtle shifts at many widespread polymorphisms that likely underlie substantial phenotypic diversity

Selective Phosphorylation Modulates the PIP2 Sensitivity of the CaM-SK Channel Complex

Phosphatidylinositol bisphosphate (PIP2) regulates the activities of many membrane proteins including ion channels through direct interactions. However, the affinity of PIP2 is so high for some channel proteins that its physiological role as a modulator has been questioned. Here we show that PIP2 is an important cofactor for activation of small conductance Ca2+-activated potassium channels (SK) by Ca2+-bound calmodulin (CaM). Removal of the endogenous PIP2 inhibits SK channels. The PIP2-binding site resides at the interface of CaM and the SK C-terminus. We further demonstrate that the affinity of PIP2 for its target proteins can be regulated by cellular signaling. Phosphorylation of CaM T79, located adjacent to the PIP2-binding site, by Casein Kinase 2 reduces the affinity of PIP2 for the CaM-SK channel complex by altering the dynamic interactions among amino acid residues surrounding the PIP2-binding site. This effect of CaM phosphorylation promotes greater channel inhibition by G-protein-mediated hydrolysis of PIP2

Clotrimazole Preferentially Inhibits Human Breast Cancer Cell Proliferation, Viability and Glycolysis

BACKGROUND: Clotrimazole is an azole derivative with promising anti-cancer effects. This drug interferes with the activity of glycolytic enzymes altering their cellular distribution and inhibiting their activities. The aim of the present study was to analyze the effects of clotrimazole on the growth pattern of breast cancer cells correlating with their metabolic profiles. METHODOLOGY/PRINCIPAL FINDINGS: Three cell lines derived from human breast tissue (MCF10A, MCF-7 and MDA-MB-231) that present increasingly aggressive profiles were used. Clotrimazole induces a dose-dependent decrease in glucose uptake in all three cell lines, with K(i) values of 114.3±11.7, 77.1±7.8 and 37.8±4.2 µM for MCF10A, MCF-7 and MDA-MB-231, respectively. Furthermore, the drug also decreases intracellular ATP content and inhibits the major glycolytic enzymes, hexokinase, phosphofructokinase-1 and pyruvate kinase, especially in the highly metastatic cell line, MDA-MB-231. In this last cell lineage, clotrimazole attenuates the robust migratory response, an effect that is progressively attenuated in MCF-7 and MCF10A, respectively. Moreover, clotrimazole reduces the viability of breast cancer cells, which is more pronounced on MDA-MB-231. CONCLUSIONS/SIGNIFICANCE: Clotrimazole presents deleterious effects on two human breast cancer cell lines metabolism, growth and migration, where the most aggressive cell line is more affected by the drug. Moreover, clotrimazole presents little or no effect on a non-tumor human breast cell line. These results suggest, at least for these three cell lines studied, that the more aggressive the cell is the more effective clotrimazole is

A novel fluorescein-bisphosphonate based diagnostic tool for the detection of hydroxyapatite in both cell and tissue models

Abstract A rapid and efficient method for the detection of hydroxyapatite (HAP) has been developed which shows superiority to existing well-established methods. This fluorescein-bisphosphonate probe is highly selective for HAP over other calcium minerals and is capable of detecting lower levels of calcification in cellular models than either hydrochloric acid-based calcium leaching assays or the Alizarin S stain. The probe has been shown to be effective in both in vitro vascular calcification models and in vitro bone calcification models. Moreover we have demonstrated binding of this probe to vascular calcification in rat aorta and to areas of microcalcification, in human vascular tissue, beyond the resolution of computed tomography in human atherosclerotic plaques. Fluorescein-BP is therefore a highly sensitive and specific imaging probe for the detection of vascular calcification, with the potential to improve not only ex vivo assessments of HAP deposition but also the detection of vascular microcalcification in humans

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies

The CMS Phase-1 pixel detector upgrade

The CMS detector at the CERN LHC features a silicon pixel detector as its innermost subdetector. The original CMS pixel detector has been replaced with an upgraded pixel system (CMS Phase-1 pixel detector) in the extended year-end technical stop of the LHC in 2016/2017. The upgraded CMS pixel detector is designed to cope with the higher instantaneous luminosities that have been achieved by the LHC after the upgrades to the accelerator during the first long shutdown in 2013–2014. Compared to the original pixel detector, the upgraded detector has a better tracking performance and lower mass with four barrel layers and three endcap disks on each side to provide hit coverage up to an absolute value of pseudorapidity of 2.5. This paper describes the design and construction of the CMS Phase-1 pixel detector as well as its performance from commissioning to early operation in collision data-taking.Peer reviewe

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29