The Role of System XC- in Cognition: The Importance of Neuron-Astrocyte Signaling

The biological basis of human intelligence is largely a mystery, but likely required evolutionary adaptations to achieve the information processing capacity needed to expand the complexity of cognition among species. The link between evolutionary expansion of signaling complexity in the brain and cognition has largely focused on neuronal mechanisms, in part because information processing has historically been attributed to these cells. However, astrocytes are emerging as a second type of brain cell that is capable of processing information due to their capacity to release glutamate and, thereby, regulate neural circuits. Hence, a modern question is whether astrocytes contributed to the signaling complexity required for sophisticated forms of cognition. The glutamate release mechanism system xc- (Sxc) is the ideal mechanism to investigate this question because it is evolutionarily novel to vertebrate species and it is expressed by astrocytes. The central hypothesis tested herein is that Sxc increased the complexity of glutamate signaling and is required for behavior requiring complex cognition. To test, a genetically modified rat with Sxc activity eliminated was generated (MSxc rats). Phenotyping revealed that loss of Sxc activity produced changes in behavior that reflect diminished cognition or top-down processing including impaired reversal learning, set-shifting, and attentional allocation. Remarkably, loss of Sxc did not impact central regulation of metabolism, Pavlovian conditioning, instrumental conditioning, locomotor activity, and novel-object recognition. Additionally, Sxc is integral to the regulation of neural networks. In the nucleus accumbens, we found that a loss of Sxc altered synaptic strength in a circuit specific manner. Further, we found that Sxc-mediated glutamate release is regulated by presynaptic (the neuropeptide PACAP), postsynaptic (endocannabinoid) and hormonal (glucocorticoids) signaling mechanisms. Further interrogation of Sxc regulation by PACAP revealed that this neuropeptide acts on both neurons and astrocytes to facilitate bidirectional neuron-astrocyte signaling between Sxc and extrasynaptic NMDA receptors. The in vivo relevance of this mechanism is established by our findings that PACAP microinjected into the nucleus accumbens attenuates cocaine-primed reinstatement, and the regulation of this behavior requires both Sxc and NMDA receptors. These findings support the possibility that future therapeutics could restore cognition by targeting astrocytes

Combined Chondroitinase and KLF7 Expression Reduce Net Retraction of Sensory and CST Axons from Sites of Spinal Injury

Axon regeneration in the central nervous system is limited both by inhibitory extracellular cues and by an intrinsically low capacity for axon growth in some CNS populations. Chondroitin sulfate proteoglycans (CSPGs) are well-studied inhibitors of axon growth in the CNS, and degradation of CSPGs by chondroitinase has been shown to improve the extension of injured axons. Alternatively, axon growth can be improved by targeting the neuron-intrinsic growth capacity through forced expression of regeneration-associated transcription factors. For example, a transcriptionally active chimera of Krüppel-like Factor 7 (KLF7) and a VP16 domain improves axon growth when expressed in corticospinal tract neurons. Here we tested the hypothesis that combined expression of chondroitinase and VP16-KLF7 would lead to further improvements in axon growth after spinal injury. Chondroitinase was expressed by viral transduction of cells in the spinal cord, while VP16-KLF7 was virally expressed in sensory neurons of the dorsal root ganglia or corticospinal tract (CST) neurons. After transection of the dorsal columns, both chondroitinase and VP16-KLF7 increased the proximity of severed sensory axons to the injury site. Similarly, after complete crush injuries, VP16-KLF7 expression increased the approach of CST axons to the injury site. In neither paradigm however, did single or combined treatment with chondroitinase or VP16-KLF7 enable regenerative growth distal to the injury. These results substantiate a role for CSPG inhibition and low KLF7 activity in determining the net retraction of axons from sites of spinal injury, while suggesting that additional factors act to limit a full regenerative response

Durability and Performance Evaluations of SuperHydrophobic and Icephobic Coatings for Tube-Fin Heat Exchangers

Mitigating frost on heat exchanger coils is key for developing high-efficiency heat pumps and enabling the widespread adoption of cold-climate heat pumps. Frost reduces heat exchanger (HX) performance by impeding airflow and adding thermal resistance, therefore taxing the system to consume more energy to satisfy temperature setpoints. Accordingly, heat pump systems have defrost cycles, which typically involve electrical heaters or hot-gas bypass systems, that consume extra energy to melt away the impeding frost/ice layer on coils. As presented in prior literature, enhanced HX surfaces (such as louvered fins or increased fin density) can accelerate frost development and thus have faster performance degradation through increased pressure drop across the coils. Thus, non-enhanced fin surfaces (such as wavy fins) with low fin densities, are typically employed in HVAC systems to minimize frosting impacts, however resulting in less compact units with lower performance under dry conditions. An alternative solution could be the use of durable superhydrophobic/icephobic coatings. This paper presents a systematic approach for testing various coatings for their viability to mitigate frost on Tube-Fin HXs. The tests shown in this paper were used as preliminary screening tests to identify coatings for a more comprehensive frost development assessment. Aluminum fin stock samples were coated by several coating vendors for understanding their hydrophobicity, icephobicity, and durability. This involved (a) an ice adhesion test to measure the maximum amount of shear force required to remove ice from the surface; (b) cyclic corrosion testing (CCT-4 standard) while qualitatively monitoring wear; (c) adhesion testing (ASTM D3359 standard) to further understand the coating-substrate bond strength; and (d) post-corrosion ice adhesion tests to characterize durability and potential performance of coatings over time in real-world environments. While most coatings maintained their wettability state after being placed in the corrosion chamber for over 1000 hours, qualitative wear and performance was shown to vary between different coatings of different chemical compositions. Variances in additives and base chemistries were shown to impact the long-term performance of the coatings. Selected coatings were then identified for a more comprehensive frost development assessment in a temperature and humidity-controlled wind-tunnel

The University of California San Francisco, Brain Metastases Stereotactic Radiosurgery (UCSF-BMSR) MRI Dataset

The University of California San Francisco Brain Metastases Stereotactic Radiosurgery (UCSF-BMSR) dataset is a public, clinical, multimodal brain MRI dataset consisting of 560 brain MRIs from 412 patients with expert annotations of 5136 brain metastases. Data consists of registered and skull stripped T1 post-contrast, T1 pre-contrast, FLAIR and subtraction (T1 pre-contrast - T1 post-contrast) images and voxelwise segmentations of enhancing brain metastases in NifTI format. The dataset also includes patient demographics, surgical status and primary cancer types. The UCSF-BSMR has been made publicly available in the hopes that researchers will use these data to push the boundaries of AI applications for brain metastases.Comment: 15 pages, 2 tables, 2 figure

CHILES: HI morphology and galaxy environment at z=0.12 and z=0.17

We present a study of 16 HI-detected galaxies found in 178 hours of observations from Epoch 1 of the COSMOS HI Large Extragalactic Survey (CHILES). We focus on two redshift ranges between 0.108 <= z <= 0.127 and 0.162 <= z <= 0.183 which are among the worst affected by radio frequency interference (RFI). While this represents only 10% of the total frequency coverage and 18% of the total expected time on source compared to what will be the full CHILES survey, we demonstrate that our data reduction pipeline recovers high quality data even in regions severely impacted by RFI. We report on our in-depth testing of an automated spectral line source finder to produce HI total intensity maps which we present side-by-side with significance maps to evaluate the reliability of the morphology recovered by the source finder. We recommend that this become a common place manner of presenting data from upcoming HI surveys of resolved objects. We use the COSMOS 20k group catalogue, and we extract filamentary structure using the topological DisPerSE algorithm to evaluate the \hi\ morphology in the context of both local and large-scale environments and we discuss the shortcomings of both methods. Many of the detections show disturbed HI morphologies suggesting they have undergone a recent interaction which is not evident from deep optical imaging alone. Overall, the sample showcases the broad range of ways in which galaxies interact with their environment. This is a first look at the population of galaxies and their local and large-scale environments observed in HI by CHILES at redshifts beyond the z=0.1 Universe.Comment: 23 pages, 12 figures, 1 interactive 3D figure, accepted to MNRA

Multiplexed and scalable super-resolution imaging of three-dimensional protein localization in size-adjustable tissues

The biology of multicellular organisms is coordinated across multiple size scales, from the subnanoscale of molecules to the macroscale, tissue-wide interconnectivity of cell populations. Here we introduce a method for super-resolution imaging of the multiscale organization of intact tissues. The method, called magnified analysis of the proteome (MAP), linearly expands entire organs fourfold while preserving their overall architecture and three-dimensional proteome organization. MAP is based on the observation that preventing crosslinking within and between endogenous proteins during hydrogel-tissue hybridization allows for natural expansion upon protein denaturation and dissociation. The expanded tissue preserves its protein content, its fine subcellular details, and its organ-scale intercellular connectivity. We use off-the-shelf antibodies for multiple rounds of immunolabeling and imaging of a tissue's magnified proteome, and our experiments demonstrate a success rate of 82% (100/122 antibodies tested). We show that specimen size can be reversibly modulated to image both inter-regional connections and fine synaptic architectures in the mouse brain.United States. National Institutes of Health (1-U01-NS090473-01

Self-Renewal of Acute Lymphocytic Leukemia Cells Is Limited by the Hedgehog Pathway Inhibitors Cyclopamine and IPI-926

Conserved embryonic signaling pathways such as Hedgehog (Hh), Wingless and Notch have been implicated in the pathogenesis of several malignancies. Recent data suggests that Hh signaling plays a role in normal B-cell development, and we hypothesized that Hh signaling may be important in precursor B-cell acute lymphocytic leukemia (B-ALL). We found that the expression of Hh pathway components was common in human B-ALL cell lines and clinical samples. Moreover, pathway activity could be modulated by Hh ligand or several pathway inhibitors including cyclopamine and the novel SMOOTHENED (SMO) inhibitor IPI-926. The inhibition of pathway activity primarily impacted highly clonogenic B-ALL cells expressing aldehyde dehydrogenase (ALDH) by limiting their self-renewal potential both in vitro and in vivo. These data demonstrate that Hh pathway activation is common in B-ALL and represents a novel therapeutic target regulating self-renewal and persistence of the malignant clone

Orbital Observations of Dust Lofted by Daytime Convective Turbulence

Over the past several decades, orbital observations of lofted dust have revealed the importance of mineral aerosols as a climate forcing mechanism on both Earth and Mars. Increasingly detailed and diverse data sets have provided an ever-improving understanding of dust sources, transport pathways, and sinks on both planets, but the role of dust in modulating atmospheric processes is complex and not always well understood. We present a review of orbital observations of entrained dust on Earth and Mars, particularly that produced by the dust-laden structures produced by daytime convective turbulence called “dust devils”. On Earth, dust devils are thought to contribute only a small fraction of the atmospheric dust budget; accordingly, there are not yet any published accounts of their occurrence from orbit. In contrast, dust devils on Mars are thought to account for several tens of percent of the planet’s atmospheric dust budget; the literature regarding martian dust devils is quite rich. Because terrestrial dust devils may temporarily contribute significantly to local dust loading and lowered air quality, we suggest that martian dust devil studies may inform future studies of convectively-lofted dust on Earth