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Astrocytes are a major category of glial support cell in the central nervous system and play a variety of essential roles in both health and disease. As our understanding of the diverse functions of these cells improves, the extent of heterogeneity between astrocyte populations has emerged as a key area of research. Retinal astrocytes, which form the direct cellular environment of retinal ganglion cells somas and axons, undergo a reactive response in both human glaucoma and animal models of the disease, yet their contributions to its pathology and progression remain relatively unknown. This gap in knowledge is largely a function of inadequate isolation techniques, driven in part by the sparseness of these cells and their similarities with the more abundant retinal Müller cells. Here, we present a novel method of isolating retinal astrocytes and enriching their RNA, tested in both normal and ocular hypertensive mice, a common model of experimental glaucoma. Our approach combines a novel enzyme assisted microdissection of retinal astrocytes with selective ribosome immunoprecipitation using the Ribotag method. Our microdissection method is rapid and preserves astrocyte morphology, resulting in a brief post-mortem interval and minimizing loss of RNA from distal regions of these cells. Both microdissection and Ribotag immunoprecipitation require a minimum of specialized equipment or reagents, and by using them in conjunction we are able to achieve > 100-fold enrichment of astrocyte RNA.

In this paper, a hardware-optimized approach to emotion recognition based on the efficient brain-inspired hyperdimensional computing (HDC) paradigm is proposed. Emotion recognition provides valuable information for human-computer interactions; however, the large number of input channels (> 200) and modalities (> 3 ) involved in emotion recognition are significantly expensive from a memory perspective. To address this, methods for memory reduction and optimization are proposed, including a novel approach that takes advantage of the combinatorial nature of the encoding process, and an elementary cellular automaton. HDC with early sensor fusion is implemented alongside the proposed techniques achieving two-class multi-modal classification accuracies of > 76% for valence and > 73% for arousal on the multi-modal AMIGOS and DEAP data sets, almost always better than state of the art. The required vector storage is seamlessly reduced by 98% and the frequency of vector requests by at least 1/5. The results demonstrate the potential of efficient hyperdimensional computing for low-power, multi-channeled emotion recognition tasks.

A potent class of isoquinoline-based α-N-heterocyclic carboxaldehyde thiosemicarbazone (HCT) compounds has been rediscovered; based upon this scaffold, three series of antiproliferative agents were synthesized through iterative rounds of methylation and fluorination modifications, with anticancer activities being potentiated by physiologically relevant levels of copper. The lead compound, HCT-13, was highly potent against a panel of pancreatic, small cell lung carcinoma, prostate cancer, and leukemia models, with IC50 values in the low-to-mid nanomolar range. Density functional theory (DFT) calculations showed that fluorination at the 6-position of HCT-13 was beneficial for ligand-copper complex formation, stability, and ease of metal-center reduction. Through a chemical genomics screen, we identify DNA damage response/replication stress response (DDR/RSR) pathways, specifically those mediated by ataxia-telangiectasia and Rad3-related protein kinase (ATR), as potential compensatory mechanism(s) of action following HCT-13 treatment. We further show that the cytotoxicity of HCT-13 is copper-dependent, that it promotes mitochondrial electron transport chain (mtETC) dysfunction, induces production of reactive oxygen species (ROS), and selectively depletes guanosine nucleotide pools. Lastly, we identify metabolic hallmarks for therapeutic target stratification and demonstrate the in vivo efficacy of HCT-13 against aggressive models of acute leukemias in mice.

BackgroundTo characterize acoustic features of an infant's cry and use machine learning to provide an objective measurement of behavioral state in a cry-translator. To apply the cry-translation algorithm to colic hypothesizing that these cries sound painful.MethodsAssessment of 1000 cries in a mobile app (ChatterBabyTM). Training a cry-translation algorithm by evaluating >6000 acoustic features to predict whether infant cry was due to a pain (vaccinations, ear-piercings), fussy, or hunger states. Using the algorithm to predict the behavioral state of infants with reported colic.ResultsThe cry-translation algorithm was 90.7% accurate for identifying pain cries, and achieved 71.5% accuracy in discriminating cries from fussiness, hunger, or pain. The ChatterBaby cry-translation algorithm overwhelmingly predicted that colic cries were most likely from pain, compared to fussy and hungry states. Colic cries had average pain ratings of 73%, significantly greater than the pain measurements found in fussiness and hunger (p

Triapine (3-AP), is an iron-binding ligand and anticancer drug that is an inhibitor of human ribonucleotide reductase (RNR). Inhibition of RNR by 3-AP results in the depletion of dNTP precursors of DNA, thereby selectively starving fast-replicating cancer cells of nucleotides for survival. The redox-active form of 3-AP directly responsible for inhibition of RNR is the Fe(II)(3-AP)2 complex. In this work, we synthesize 12 analogs of 3-AP, test their inhibition of RNR in vitro, and study the electronic properties of their iron complexes. The reduction and oxidation events of 3-AP iron complexes that are crucial for the inhibition of RNR are modeled with solution studies. We monitor the pH necessary to induce reduction in iron complexes of 3-AP analogs in a reducing environment, as well as the kinetics of oxidation in an oxidizing environment. The oxidation state of the complex is monitored using UV-Vis spectroscopy. Isoquinoline analogs of 3-AP favor the maintenance of the biologically active reduced complex and possess oxidation kinetics that allow redox cycling, consistent with their effective inhibition of RNR seen in our in vitro experiments. In contrast, methylation on the thiosemicarbazone secondary amine moiety of 3-AP produces analogs that form iron complexes with much higher redox potentials, that do not redox cycle, and are inactive against RNR in vitro. The catalytic subunit of human Ribonucleotide Reductase (RNR), contains a tyrosyl radical in the enzyme active site. Fe(II) complexes of 3-AP and its analogs can quench the radical and, subsequently, inactivate RNR. The potency of RNR inhibitors is highly dependent on the redox properties of the iron complexes, which can be tuned by ligand modifications. Complexes are found to be active within a narrow redox window imposed by the cellular environment.

Drinking water contamination with heavy metals, particularly lead, is a persistent problem worldwide with grave public health consequences. Existing purification methods often cannot address this problem quickly and economically. Here we report a cheap, water stable metal-organic framework/polymer composite, Fe-BTC/PDA, that exhibits rapid, selective removal of large quantities of heavy metals, such as Pb2+ and Hg2+, from real world water samples. In this work, Fe-BTC is treated with dopamine, which undergoes a spontaneous polymerization to polydopamine (PDA) within its pores via the Fe3+ open metal sites. The PDA, pinned on the internal MOF surface, gains extrinsic porosity, resulting in a composite that binds up to 1634 mg of Hg2+ and 394 mg of Pb2+ per gram of composite and removes more than 99.8% of these ions from a 1 ppm solution, yielding drinkable levels in seconds. Further, the composite properties are well-maintained in river and seawater samples spiked with only trace amounts of lead, illustrating unprecedented selectivity. Remarkably, no significant uptake of competing metal ions is observed even when interferents, such as Na+, are present at concentrations up to 14 000 times that of Pb2+. The material is further shown to be resistant to fouling when tested in high concentrations of common organic interferents, like humic acid, and is fully regenerable over many cycles.