Coordinated migration and placement of interneurons and projection neurons lead to functional connectivity in the cerebral cortex; defective neuronal migration and the resultant connectivity changes ...underlie the cognitive defects in a spectrum of neurological disorders. Here we show that primary cilia play a guiding role in the migration and placement of postmitotic interneurons in the developing cerebral cortex and that this process requires the ciliary protein, Arl13b. Through live imaging of interneuronal cilia, we show that migrating interneurons display highly dynamic primary cilia and we correlate cilia dynamics with the interneuron's migratory state. We demonstrate that the guidance cue receptors essential for interneuronal migration localize to interneuronal primary cilia, but their concentration and dynamics are altered in the absence of Arl13b. Expression of Arl13b variants known to cause Joubert syndrome induce defective interneuronal migration, suggesting that defects in cilia-dependent interneuron migration may in part underlie the neurological defects in Joubert syndrome patients.
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► Arl13b cilia activity is required for interneuronal migration and placement ► Ciliary dynamics increase during decision-making pauses in migration ► Arl13b regulates guidance receptor localization and movement selectively in cilia ► Joubert Syndrome-causing Arl13b mutations affect interneuronal development
Higginbotham et al. find that the location, directionality, and length of primary cilia are dynamically regulated during decision-making pauses in interneuronal migration. The small GTPase Arl13b is required in cilia for this regulation, for ciliary localization of guidance receptors, and for robust migration. Joubert Syndrome-causing Arl13b mutations disrupt cortical development.
According to the free radical theory, aging can be considered as a progressive, inevitable process partially related to the accumulation of oxidative damage into biomolecules – nucleic acids, lipids, ...proteins or carbohydrates – due to an imbalance between prooxidants and antioxidants in favor of the former. More recently also the pathogenesis of several diseases has been linked to a condition of oxidative stress. In this review we focus our attention on the evidence of oxidative stress in aging brain, some of the most important neurodegenerative diseases – Alzheimer's disease (AD), mild cognitive impairment (MCI), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) – and in two common and highly disabling vascular pathologies—stroke and cardiac failure. Particular attention will be given to the current knowledge about the biomarkers of oxidative stress that can be possibly used to monitor their severity and outcome.
6061 O Al alloy foils were welded to form monolithic and SiC fibre-embedded samples using the ultrasonic consolidation (UC) process. Contact pressures of 135, 155 and 175
MPa were investigated at 20
...kHz frequency, 50% of the oscillation amplitude, 34.5
mm
s
−1 sonotrode velocity and 20
°C. Deformed microstructures were analysed using electron backscatter diffraction (EBSD). At all contact pressures deformation occurs by non-steady state dislocation glide. Dynamic recovery is active in the upper and lower foils. Friction at the welding interface, instantaneous internal temperatures (0.5–0.8 of the melting temperature,
T
m), contact pressure and fast strain rates result in transient microstructures and grain size reduction by continuous dynamic recrystallization (CDRX) within the bonding zone. Bonding occurs by local grain boundary migration, which allows diffusion and atom interlocking across the contact between two clean surfaces. Textures weaken with increasing contact pressure due to increased strain hardening and different grain rotation rates. High contact pressures enhance dynamic recovery and CDRX. Deformation around the fibre is intense within 50
μm and extends to 450
μm from it.
This study evaluated the impact of an abandoned Ag mine on the quality of surface and groundwater. The mining site of Huautla is in south Morelos State, central Mexico. Ag–Pb–Zn and Au–Cu sulfide ...ores were mined in the district. The ores were characterized by the presence of Ag, galena (PbS), sphalerite (ZnS), and stromeyerite (CuAgS). Ag was the metal of greater interest. Other metals included Cu, Pb, Zn, and Au. Mining activities stopped in the early 1990s when the market price of Ag decreased; the abandoned mines then were flooded by rising groundwater levels. Because of the urgent demand for water by the inhabitants in the area, this water has been used as drinking water and as waterholes for livestock. Water sampling points included abandoned mines (América, Pajáro, Santiago, Tlachichilpa, and San Francisco), dams, and dug wells. The greatest concentrations of As and other toxic chemical elements (Fe, Mn, Pb, Cd, F) were detected in groundwater samples from flooded mines. The presence of these elements was related to the rock–water interaction process. The oxidation of sulfides appears to be the cause of increased metal concentrations in groundwater samples from flooded mine. Other possible water–rock interaction processes that can control the presence of arsenic in groundwater were the adsorption of arsenic in iron oxyhydroxides, the adsorption in carbonates, and/or coprecipitation with calcite. In the case of the San Francisco and América mines, the oxidation conditions, low correlation of As with SO
4
2−
and Fe
2+
, and concentrations of silica indicate that the presence of As in the groundwater could be due also to competition for adsorption sites.
The occurrence of crystallized and glassy melt inclusions (MI) in high‐grade, partially melted metapelites and metagraywackes has opened up new possibilities to investigate anatectic processes. The ...present study focuses on three case studies: khondalites from the Kerala Khondalite Belt (India), the Ronda migmatites (Spain), and the Barun Gneiss (Nepal Himalaya). The results of a detailed microstructural investigation are reported, along with some new microchemical data on the bulk composition of MI. These inclusions were trapped within peritectic garnet and ilmenite during crystal growth and are therefore primary inclusions. They are generally isometric and very small in size, mostly ≤15 μm, and only rarely reaching 30 μm; they occur in clusters. In most cases inclusions are crystallized (‘nanogranites’) and contain a granitic phase assemblage with quartz, feldspar and one or two mica depending on the particular case study, commonly with accessory phases (mainly zircon, apatite, rutile). In many cases the polycrystalline aggregates that make up the nanogranites show igneous microstructures, e.g. granophyric intergrowths, micrographic quartz in K‐feldspar and cuneiform rods of quartz in plagioclase. Further evidence for the former presence of melt within the investigated inclusions consists of melt pseudomorphs, similar to those recognized at larger scale in the host migmatites. Moreover, partially crystallized inclusions are locally abundant and together with very small (≤8 μm) glassy inclusions may occur in the same clusters. Both crystallized and partially crystallized inclusions often display a diffuse nanoporosity, which may contain fluids, depending on the case study. After entrapment, inclusions underwent limited microstructural modifications, such as shape maturation, local necking down processes, and decrepitation (mainly in the Barun Gneiss), which did not influence their bulk composition. Re‐homogenized nanogranites and glassy inclusions show a leucogranitic and peraluminous composition, consistent with the results of partial melting experiments on metapelites and metagraywackes. Anatectic MI should therefore be considered as a new and important opportunity to understand the partial melting processes.
Mesenchymal Stem Cells (MSCs) are a population of adherent cells that can differentiate into mesenchymal lineage populations (cartilage, bone and fat tissue). In addition, they seem to be able to ...differentiate also into a broader type of lineages other than the original mesodermal germ layer. Bone marrow MSCs are a standard in the field of adult stem cell biology and clinical applications; however adipose-derived MSCs are becoming an attractive alternative due to their minimally invasive accessibility and availability in the body. MSCs modulate several effector immune functions by interacting both with innate and adoptive immune responses. Several local signals from the tissue microenvironment, together with cytokine and soluble factors released by MSCs influence anti-inflammatory and tissue repair properties of infused MSCs. Therefore, cellular therapies utilizing ex vivo expanded MSCs may be an interesting approach for inflammatory and autoimmune diseases. Biosafety is still one of the most important aspects; therefore the production of clinical-grade MSCs requires the careful identification and control of all the phases of cell manipulation and release. Many clinical applications of adult MSCs are in progress and are using bone marrow or adipose tissue-derived MSCs for the treatment of Graft Versus Host Disease (GVHD), inflammatory joint diseases and osteocartilagineous defects, digestive tract, cardiovascular and neurological diseases.
The regulatory GTPase Arl13b localizes to primary cilia, where it regulates Sonic hedgehog (Shh) signaling. Missense mutations in ARL13B can cause the ciliopathy Joubert syndrome, while the mouse ...null allele is embryonic lethal. We used mouse embryonic fibroblasts as a system to determine the effects of Arl13b mutations on Shh signaling. We tested a total of seven different mutants, three JS-causing variants, two point mutants predicted to alter guanine nucleotide handling, one that disrupts cilia localization, and one that prevents palmitoylation and thus membrane binding, in assays of transcriptional and non-transcriptional Shh signaling. We found that mutations disrupting Arl13b's palmitoylation site, cilia localization signal, or GTPase handling altered the Shh response in distinct assays of transcriptional or non-transcriptional signaling. In contrast, JS-causing mutations in Arl13b did not affect Shh signaling in these same assays, suggesting these mutations result in more subtle defects, likely affecting only a subset of signaling outputs. Finally, we show that restricting Arl13b from cilia interferes with its ability to regulate Shh-stimulated chemotaxis, despite previous evidence that cilia themselves are not required for this non-transcriptional Shh response. This points to a more complex relationship between the ciliary and non-ciliary roles of this regulatory GTPase than previously envisioned.
The stepover of adjacent deposition lines (or beads), when stacking layers to build a 3D-solid shape, is found to be of great importance to minimize voidage and so, improving density of parts ...produced by the Directed Energy Deposition (DED) process. During such process, in which the stacking of layers occurs, the complex thermal activity of metal deposition affects the part geometry, microstructure, physical and mechanical properties. The correlation between deposition path, bead stepover, and the direct effect on the part density, microstructure and geometry distortions are yet to be found in the literature. Therefore, the aim of this study is to evaluate the effect of deposition paths and bead stepover on the final part geometry form, microhardness and density. In order to do so, four deposition paths (linear, zigzag, chessboard and contour) and beads stepover of 0.44 mm and 0.55 mm were performed on the production of Stainless Steel 316L cubes by a 5-axis laser based DED BeAM Machine Magic800 with laser spot size of 0.80 mm. The paths shown considerable influence on the variation of both final part geometry and density. Contour (spiral-like) was the path, which produced workpieces with finer form and finishing, with density and microhardness closer to the conventional AISI 316L material. The bead stepover was also found to influence the surface finishing, as larger critical valleys between adjacent beads were noticed when using the higher stepover value.
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