Adenosine Inhibits the Excitatory Synaptic Inputs to Basal Forebrain Cholinergic, GABAergic, and Parvalbumin Neurons in Mice

Coffee and tea contain the stimulants caffeine and theophylline. These compounds act as antagonists of adenosine receptors. Adenosine promotes sleep and its extracellular concentration rises in association with prolonged wakefulness, particularly in the basal forebrain (BF) region involved in activating the cerebral cortex. However, the effect of adenosine on identified BF neurons, especially non-cholinergic neurons, is incompletely understood. Here we used whole-cell patch-clamp recordings in mouse brain slices prepared from two validated transgenic mouse lines with fluorescent proteins expressed in GABAergic or parvalbumin (PV) neurons to determine the effect of adenosine. Whole-cell recordings were made from BF cholinergic neurons and from BF GABAergic and PV neurons with the size (>20 μm) and intrinsic membrane properties (prominent H-currents) corresponding to cortically projecting neurons. A brief (2 min) bath application of adenosine (100 μM) decreased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (EPSCs) in all groups of BF cholinergic, GABAergic, and PV neurons we recorded. In addition, adenosine decreased the frequency of miniature EPSCs in BF cholinergic neurons. Adenosine had no effect on the frequency of spontaneous inhibitory postsynaptic currents in cholinergic neurons or GABAergic neurons with large H-currents but reduced them in a group of GABAergic neurons with smaller H-currents. All effects of adenosine were blocked by a selective, adenosine A1 receptor antagonist, cyclopentyltheophylline (CPT, 1 μM). Adenosine had no postsynaptic effects. Taken together, our work suggests that adenosine promotes sleep by an A1 receptor-mediated inhibition of glutamatergic inputs to cortically projecting cholinergic and GABA/PV neurons. Conversely, caffeine and theophylline promote attentive wakefulness by inhibiting these A1 receptors in BF thereby promoting the high-frequency oscillations in the cortex required for attention and cognition

Examining the Externalities of Highway Capacity Expansions in California: An Analysis of Land Use and Land Cover (LULC) Using Remote Sensing Technology

There are over 590,000 bridges dispersed across the roadway network that stretches across the United States alone. Each bridge with a length of 20 feet or greater must be inspected at least once every 24 months, according to the Federal Highway Act (FHWA) of 1968. This research developed an artificial intelligence (AI)-based framework for bridge and road inspection using drones with multiple sensors collecting capabilities. It is not sufficient to conduct inspections of bridges and roads using cameras alone, so the research team utilized an infrared (IR) camera along with a high-resolution optical camera. In many instances, the IR camera can provide more details to the interior structural damages of a bridge or a road surface than an optical camera, which is more suitable for inspecting damages on the surface of a bridge or a road. In addition, the drone inspection system is equipped with a minicomputer that runs Machine Learning algorithms. These algorithms enable autonomous drone navigation, image capture of the bridge or road structure, and analysis of the images. Whenever any damage is detected, the location coordinates are saved. Thus, the drone can self-operate and carry out the inspection process using advanced AI algorithms developed by the research team. The experimental results reveal the system can detect potholes with an average accuracy of 84.62% using the visible light camera and 95.12% using a thermal camera. This developed bridge and road inspection framework can save time, money, and lives by automating and having drones conduct major inspection operations in place of humans

The regulation of the autophagic network and its implications for human disease

Autophagy has attracted a lot of attention in recent years. More and more proteins and signaling pathways have been discovered that somehow feed into the autophagy regulatory pathways. Regulation of autophagy is complex and condition-specific, and in several diseases, autophagic fluxes are changed. Here, we review the most well-established concepts in this field as well as the reported signaling pathways or components which steer the autophagy machinery. Furthermore, we will highlight how autophagic fluxes are changed in various diseases either as cause for or as response to deal with an altered cellular homeostasis and how modulation of autophagy might be used as potential therapy for such diseases

Use of fecal samples for microbiome analysis in bumblebees

Due to declines in bumblebees and other pollinators, there is an increased need for monitoring of bee populations and health. The gut microbiome is integral to bumblebee health, with roles in nutrition and immune function, including interactions with pathogens, which have been shown to contribute to bee declines. Noninvasive methods enable deeper sampling of bee populations with less impact on sensitive populations. Wider sampling of bumblebee microbiomes would provide information on bee health while expanding the phylogenetic and ecological scope of bee microbiome research. Previous studies have demonstrated the use of fecal samples to obtain bee DNA, and that fecal microbiomes are able to recover gut microbiomes. This study demonstrates the use of fecal samples for comparative microbiome analyses using two bumblebee species from North AmericaEcology, Evolution and Behavio

The European Court of Justice and National Courts' Approach to the Kompetenz-Kompetenz Question: The Cases of Germany and the UK

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A pyrazolopyran derivative preferentially inhibits the activity of human cytosolic hydroxymethyltransferase and induces cell death in lung cancer cells

Serine hydroxymethyltransferase (SHMT) is a central enzyme in the metabolic reprogramming of cancer cells, providing activated one-carbon units in the serine-glycine one-carbon metabolism. Previous studies demonstrated that the cytoplasmic isoform of SHMT (SHMT1) plays a relevant role in lung cancer. SHMT1 is overexpressed in lung cancer patients and NSCLC cell lines. Moreover, SHMT1 is required to maintain DNA integrity. Depletion in lung cancer cell lines causes cell cycle arrest and uracil accumulation and ultimately leads to apoptosis. We found that a pyrazolopyran compound, namely 2.12, preferentially inhibits SHMT1 compared to the mitochondrial counterpart SHMT2. Computational and crystallographic approaches suggest binding at the active site of SHMT1 and a competitive inhibition mechanism. A radio isotopic activity assay shows that inhibition of SHMT by 2.12 also occurs in living cells. Moreover, administration of 2.12 in A549 and H1299 lung cancer cell lines causes apoptosis at LD50 34 μM and rescue experiments underlined selectivity towards SHMT1. These data not only further highlight the relevance of the cytoplasmic isoform SHMT1 in lung cancer but, more importantly, demonstrate that, at least in vitro, it is possible to find selective inhibitors against one specific isoform of SHMT, a key target in metabolic reprogramming of many cancer types

The opaque heart of the galaxy IC 860: Analogous protostellar, kinematics, morphology, and chemistry

Compact Obscured Nuclei (CONs) account for a significant fraction of the population of luminous and ultraluminous infrared galaxies (LIRGs and ULIRGs). These galaxy nuclei are compact, with radii of 10-100 pc, with large optical depths at submm and far-infrared wavelengths, and characterized by vibrationally excited HCN emission. It is not known what powers the large luminosities of the CON host galaxies because of the extreme optical depths towards their nuclei. CONs represent an extreme phase of nuclear growth, hiding either a rapidly accreting supermassive black hole or an abnormal mode of star formation. Regardless of their power source, the CONs allow us to investigate the processes of nuclear growth in galaxies. Here we apply principal component analysis (PCA) tomography to high-resolution (000:06) ALMA observations at frequencies 245 to 265 GHz of the nearby CON (59 Mpc) IC 860. PCA is a technique to unveil correlation in the data parameter space, and we apply it to explore the morphological and chemical properties of species in our dataset. The leading principal components reveal morphological features in molecular emission that suggest a rotating, infalling disk or envelope, and an outflow analogous to those seen in Galactic protostars. One particular molecule of astrochemical interest is methanimine (CH2NH), a precursor to glycine, three transitions of which have been detected towards IC 860.We estimate the average CH2NH column density towards the nucleus of IC 860 to be _1017cm2, with an abundance exceeding 108 relative to molecular hydrogen, using the rotation diagram method and non-LTE radiative transfer models. This CH2NH abundance is consistent with those found in hot cores of molecular clouds in the Milky Way. Our analysis suggests that CONs are an important stage of chemical evolution in galaxies, that are chemically and morphologically similar to Milky Way hot cores

Rest-frame UV line emission from the intergalactic medium at 2<z<5

Rest-frame UV emission lines offer the possibility to directly image the gas around high-redshift galaxies with upcoming optical instruments. We use a suite of large, hydrodynamical simulations to predict the nature and detectability of emission lines from the intergalactic medium at 2<z<5. The brightest emission comes from HI Ly-alpha and the strongest metal line, CIII, is about an order of magnitude fainter, although HI Ly-alpha may be fainter if the gas is self-shielded to the UV background or if dust is important. The highest surface brightness regions for CIV, SiIII, SiIV and OVI are fainter than CIII by factors of a few. The NV and NeVIII lines, as well as HeII H-alpha, are substantially weaker but their maximum surface brightnesses still exceed 100 photon/cm^2/s/sr at z=2 (for 2" pixels). Lower ionisation lines arise in denser and colder gas that produces clumpier emission. The brightest HI Ly-alpha emission arises in highly overdense gas, but the highest surface brightness emission from high-ionisation metal lines traces a wider range of overdensities. Bright metal-line emission traces gas with temperatures close to the peak of the corresponding emissivity curve. While HI Ly-alpha, HeII H-alpha, CIII, SiIII, and SiIV are excellent probes of cold accretion flows and the colder parts of outflows, CIV, NV, OVI, and NeVIII are powerful tracers of the diffuse WHIM and galactic winds. A comparison of results from simulations with varying physical prescriptions demonstrates that the predictions for the brighter metal-line emission are robust to within factors of a few. Several emission lines from the high-redshift IGM will become detectable in the near future, possibly starting with the Cosmic Web Imager on Palomar. MUSE and the Keck Cosmic Web Imager have the potential to revolutionise studies of the interactions between high-redshift galaxies and their environment. (Abridged)Comment: 21 pages, 17 figures. Accepted for publication by MNRA

Minimalist Design of Wireframe DNA Nanotubes: Tunable Geometry, Size, Chirality, and Dynamics

DNA nanotubes (NTs) have attracted extensive interest as artificial cytoskeletons for biomedical, synthetic biology, and materials applications. Here, we report the modular design and assembly of a minimalist yet robust DNA wireframe nanotube with tunable cross-sectional geometry, cavity size, chirality, and length, while using only four DNA strands. We introduce an h-motif structure incorporating double-crossover (DX) tile-like DNA edges to achieve structural rigidity and provide efficient self-assembly of h-motif-based DNA nanotube (H-NT) units, thus producing programmable, micrometer-long nanotubes. We demonstrate control of the H-NT nanotube length via short DNA modulators. Finally, we use an enzyme, RNase H, to take these structures out of equilibrium and trigger nanotube assembly at a physiologically relevant temperature, underlining future cellular applications. The minimalist H-NTs can assemble at near-physiological salt conditions and will serve as an easily synthesized, DNA-economical modular template for biosensors, plasmonics, or other functional materials and as cost-efficient drug-delivery vehicles for biomedical applications.A minimalist design of robust DNA nanotubes from only 4 DNA strands, with tunable geometry, chirality, length, and assembly dynamics is reported. The method leads to robust nanotubes under physiologically relevant conditions, as cost-efficient nanomaterial templates or drug-delivery vehicles.+imag

Kinetic and Structural Studies of Phosphodiesterase-8A and Implication on the Inhibitor Selectivity † ‡

Cyclic nucleotide phosphodiesterase-8 (PDE8) is a family of cAMP-specific enzymes and plays important roles in many biological processes, including T-cell activation, testosterone production, adrenocortical hyperplasia, and thyroid function. However, no PDE8 selective inhibitors are available for trial treatment of human diseases. Here we report kinetic properties of the highly active PDE8A1 catalytic domain prepared from refolding and its crystal structures in the unliganded and 3-isobutyl-1-methylxanthine (IBMX) bound forms at 1.9 and 2.1 Å resolutions, respectively. The PDE8A1 catalytic domain has KM of 1.8 μM, Vmax of 6.1 μmol/min/mg, kcat of 4.0 s−1 for cAMP, and KM of 1.6 mM, Vmax of 2.5 μmol/min/mg, kcat of 1.6 s−1 for cGMP, thus indicating that the substrate specificity of PDE8 is dominated by KM. The structure of the PDE8A1 catalytic domain has similar topology as those of other PDE families, but contains two extra helices around Asn685-Thr710. Since this fragment is distant from the active site of the enzyme, its impact on the catalysis is unclear. The PDE8A1 catalytic domain is insensitive to the IBMX inhibition (IC50 = 700 μM). The unfavorable interaction of IBMX in the PDE8A1-IBMX structure suggests an important role of Tyr748 in the inhibitor binding. Indeed, the mutation of Tyr748 to phenylalanine increases the PDE8A1 sensitivity to several non-selective or family-selective PDE inhibitors. Thus, the structural and mutagenesis studies provide not only insight into the enzymatic properties, but also guidelines for design of PDE8 selective inhibitors