Notes

Ball-Milling-Enabled Reactivity associated with Manganese Metal*.
Of five known adenovirus genera, high-resolution structures are available only for mammalian-infecting mastadenoviruses. We present the first high-resolution structure of an adenovirus with nonmammalian host lizard atadenovirus LAdV-2. We find a large conformational difference in the internal vertex protein IIIa between mast- and atadenoviruses, induced by the presence of an extended polypeptide. This polypeptide, and α-helical clusters beneath the facet, likely correspond to genus-specific proteins LH2 and p32k. Another genus-specific protein, LH3, with a fold typical of bacteriophage tailspikes, contacts the capsid surface via a triskelion structure identical to that used by mastadenovirus protein IX, revealing a conserved capsid-binding motif and an ancient gene duplication event. Our data also suggest that mastadenovirus E1B-55 K was exapted from the atadenovirus-like LH3 protein. This work provides new information on the evolution of adenoviruses, emphasizing the importance of minor coat proteins for determining specific physicochemical properties of virions and most likely their tropism.Materials (e.g., brick or wood) are generally perceived as unintelligent. Even the highly researched "smart" materials are only capable of extremely primitive analytical functions (e.g., simple logical operations). Here, a material is shown to have the ability to perform (i.e., without a computer), an advanced mathematical operation in calculus the temporal derivative. It consists of a stimuli-responsive material coated asymmetrically with an adaptive impermeable layer. Its ability to analyze the derivative is shown by experiments, numerical modeling, and theory (i.e., scaling between derivative and response). This class of freestanding stimuli-responsive materials is demonstrated to serve effectively as a derivative controller for controlled delivery and self-regulation. Its fast response realizes the same designed functionality and efficiency as complex industrial derivative controllers widely used in manufacturing. These results illustrate the possibility to associate specifically designed materials directly with higher concepts of mathematics for the development of "intelligent" material-based systems.Intake of processed foods has increased markedly over the past decades, coinciding with increased microvascular diseases such as chronic kidney disease (CKD) and diabetes. Here, we show in rodent models that long-term consumption of a processed diet drives intestinal barrier permeability and an increased risk of CKD. Inhibition of the advanced glycation pathway, which generates Maillard reaction products within foods upon thermal processing, reversed kidney injury. Consequently, a processed diet leads to innate immune complement activation and local kidney inflammation and injury via the potent proinflammatory effector molecule complement 5a (C5a). In a mouse model of diabetes, a high resistant starch fiber diet maintained gut barrier integrity and decreased severity of kidney injury via suppression of complement. These results demonstrate mechanisms by which processed foods cause inflammation that leads to chronic disease.The Cantor high-entropy alloy (HEA) of CrMnFeCoNi is a solid solution with a face-centered cubic structure. While plastic deformation in this alloy is usually dominated by dislocation slip and deformation twinning, our in situ straining transmission electron microscopy (TEM) experiments reveal a crystalline-to-amorphous phase transformation in an ultrafine-grained Cantor alloy. We find that the crack-tip structural evolution involves a sequence of formation of the crystalline, lamellar, spotted, and amorphous patterns, which represent different proportions and organizations of the crystalline and amorphous phases. Such solid-state amorphization stems from both the high lattice friction and high grain boundary resistance to dislocation glide in ultrafine-grained microstructures. The resulting increase of crack-tip dislocation densities promotes the buildup of high stresses for triggering the crystalline-to-amorphous transformation. We also observe the formation of amorphous nanobridges in the crack wake. These amorphization processes dissipate strain energies, thereby providing effective toughening mechanisms for HEAs.We investigated the spatial representation of covert attention and movement planning in monkeys performing a task that used symbolic cues to decouple the locus of covert attention from the motor target. In the three frontal areas studied, most spatially tuned neurons reflected either where attention was allocated or the planned saccade. Neurons modulated by both covert attention and the motor plan were in the minority. Such dual-purpose neurons were especially rare in premotor and prefrontal cortex but were more common just rostral to the arcuate sulcus. The existence of neurons that indicate where the monkey was attending but not its movement goal runs counter to the idea that the control of spatial attention is entirely reliant on the neuronal circuits underlying motor planning. Rather, the presence of separate neuronal populations for each cognitive process suggests that endogenous attention is under flexible control and can be dissociated from motor intention.Xinjiang is a key region in northwestern China, connecting East and West Eurasian populations and cultures for thousands of years. To understand the genetic history of Xinjiang, we sequenced 237 complete ancient human mitochondrial genomes from the Bronze Age through Historical Era (41 archaeological sites). Overall, the Bronze Age Xinjiang populations show high diversity and regional genetic affinities with Steppe and northeastern Asian populations along with a deep ancient Siberian connection for the Tarim Basin Xiaohe individuals. Selleck Ilomastat In the Iron Age, in general, Steppe-related and northeastern Asian admixture intensified, with North and East Xinjiang populations showing more affinity with northeastern Asians and South Xinjiang populations showing more affinity with Central Asians. The genetic structure observed in the Historical Era of Xinjiang is similar to that in the Iron Age, demonstrating genetic continuity since the Iron Age with some additional genetic admixture with populations surrounding the Xinjiang region.Gene replacement approaches are leading to a revolution in the treatment of previously debilitating monogenic neurological conditions. However, the application of gene therapy to complex polygenic conditions has been limited. Down-regulation or dysfunction of receptor expression in the disease state or in the presence of excess ligand has been shown to compromise therapeutic efficacy. Here, we offer evidence that combined overexpression of both brain-derived neurotrophic factor and its receptor, tropomyosin receptor kinase B, is more effective in stimulating axonal transport than either receptor administration or ligand administration alone. We also show efficacy in experimental glaucoma and humanized tauopathy models. Simultaneous administration of a ligand and its receptor by a single gene therapy vector overcomes several problems relating to ligand deficiency and receptor down-regulation that may be relevant to multiple neurodegenerative diseases. This approach shows promise as a strategy to target intrinsic mechanisms to improve neuronal function and facilitate repair.Large airbursts, the most frequent hazardous impact events, are estimated to occur orders of magnitude more frequently than crater-forming impacts. However, finding traces of these events is impeded by the difficulty of identifying them in the recent geological record. Here, we describe condensation spherules found on top of Walnumfjellet in the Sør Rondane Mountains, Antarctica. Affinities with similar spherules found in EPICA Dome C and Dome Fuji ice cores suggest that these particles were produced during a single-asteroid impact ca. 430 thousand years (ka) ago. The lack of a confirmed crater on the Antarctic ice sheet and geochemical and 18O-poor oxygen isotope signatures allow us to hypothesize that the impact particles result from a touchdown event, in which a projectile vapor jet interacts with the Antarctic ice sheet. Numerical models support a touchdown scenario. This study has implications for the identification and inventory of large cosmic events on Earth.Lacunae and canaliculi spaces of osteocytes are remarkably well preserved in fossilized bone and serve as an established proxy for bone cells. The earliest bone in the fossil record is acellular (anosteocytic), followed by cellular (osteocytic) bone in the jawless relatives of jawed vertebrates, the osteostracans, about 400 million years ago. Virtually nothing is known about the physiological pressures that would have initially favored osteocytic over anosteocytic bone. We apply focused ion beam-scanning electron microscopy tomography combined with machine learning for cell detection and segmentation to image fossil cell spaces. Novel three-dimensional high-resolution images reveal areas of low density around osteocyte lacunae and their canaliculi in osteostracan bone. This provides evidence for demineralization that would have occurred in vivo as part of osteocytic osteolysis, a mechanism of mineral homeostasis, supporting the hypothesis that a physiological demand for phosphorus was the principal driver in the initial evolution of osteocytic bone.Huntington disease (HD) damages the corticostriatal circuitry in large part by impairing transport of brain-derived neurotrophic factor (BDNF). We hypothesized that improving vesicular transport of BDNF could slow or prevent disease progression. We therefore performed selective proteomic analysis of vesicles transported within corticostriatal projecting neurons followed by in silico screening and identified palmitoylation as a pathway that could restore defective huntingtin-dependent trafficking. Using a synchronized trafficking assay and an HD network-on-a-chip, we found that increasing brain palmitoylation via ML348, which inhibits the palmitate-removing enzyme acyl-protein thioesterase 1 (APT1), restores axonal transport, synapse homeostasis, and survival signaling to wild-type levels without toxicity. In human HD induced pluripotent stem cell-derived cortical neurons, ML348 increased BDNF trafficking. In HD knock-in mice, it efficiently crossed the blood-brain barrier to restore palmitoylation levels and reverse neuropathology, locomotor deficits, and anxio-depressive behaviors. APT1 and its inhibitor ML348 thus hold therapeutic interest for HD.Cognitive impairment in schizophrenia (CIAS) is the most critical predictor of functional outcome. Limited understanding of the cellular mechanisms of CIAS hampers development of more effective treatments. We found that in subchronic phencyclidine (scPCP)-treated mice, an animal model that mimics CIAS, the reversal potential of GABAA currents in pyramidal neurons of the infralimbic prefrontal cortex (ILC) shifts from hyperpolarizing to depolarizing, the result of increased expression of the chloride transporter NKCC1. Further, we found that in scPCP mice, the NKCC1 antagonist bumetanide normalizes GABAA current polarity ex vivo and improves performance in multiple cognitive tasks in vivo. This behavioral effect was mimicked by selective, bilateral, NKCC1 knockdown in the ILC. Thus, we show that depolarizing GABAA currents in the ILC contributes to cognitive impairments in scPCP mice and suggest that bumetanide, an FDA-approved drug, has potential to treat or prevent CIAS and other components of the schizophrenia syndrome.
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