CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase.

Selective neuronal loss is a hallmark of neurodegenerative diseases, which, counterintuitively, are often caused by mutations in widely expressed genes. Charcot-Marie-Tooth (CMT) diseases are the most common hereditary peripheral neuropathies, for which there are no effective therapies. A subtype of these diseases--CMT type 2D (CMT2D)--is caused by dominant mutations in GARS, encoding the ubiquitously expressed enzyme glycyl-transfer RNA (tRNA) synthetase (GlyRS). Despite the broad requirement of GlyRS for protein biosynthesis in all cells, mutations in this gene cause a selective degeneration of peripheral axons, leading to deficits in distal motor function. How mutations in GlyRS (GlyRS(CMT2D)) are linked to motor neuron vulnerability has remained elusive. Here we report that GlyRS(CMT2D) acquires a neomorphic binding activity that directly antagonizes an essential signalling pathway for motor neuron survival. We find that CMT2D mutations alter the conformation of GlyRS, enabling GlyRS(CMT2D) to bind the neuropilin 1 (Nrp1) receptor. This aberrant interaction competitively interferes with the binding of the cognate ligand vascular endothelial growth factor (VEGF) to Nrp1. Genetic reduction of Nrp1 in mice worsens CMT2D symptoms, whereas enhanced expression of VEGF improves motor function. These findings link the selective pathology of CMT2D to the neomorphic binding activity of GlyRS(CMT2D) that antagonizes the VEGF-Nrp1 interaction, and indicate that the VEGF-Nrp1 signalling axis is an actionable target for treating CMT2D.

Microscopy ambient ionization top-down mass spectrometry reveals developmental patterning.

There is immense cellular and molecular heterogeneity in biological systems. Here, we demonstrate the utility of integrating an inverted light microscope with an ambient ionization source, nanospray electrospray desorption ionization, attached to a high-resolution mass spectrometer to characterize the molecular composition of mouse spinal cords. We detected a broad range of molecules, including peptides and proteins, as well as metabolites such as lipids, sugars, and other small molecules, including S-adenosyl methionine and glutathione, through top-down MS. Top-down analysis revealed variation in the expression of Hb, including the transition from fetal to adult Hb and heterogeneity in Hb subunits consistent with the genetic diversity of the mouse models. Similarly, temporal changes to actin-sequestering proteins ß-thymosins during development were observed. These results demonstrate that interfacing microscopy with ambient ionization provides the means to perform targeted in situ ambient top-down mass spectral analysis to study the pattern of proteins, lipids, and sugars in biologically heterogeneous samples.

High-productivity lipid production using mixed trophic state cultivation of Auxenochlorella (Chlorella) protothecoides.

A mixed trophic state production process for algal lipids for use as feedstock for renewable biofuel production was developed and deployed at subpilot scale using a green microalga, Auxenochlorella (Chlorella) protothecoides. The process is composed of two separate stages: (1) the photoautotrophic stage, focused on biomass production in open ponds, and (2) the heterotrophic stage focused on lipid production and accumulation in aerobic bioreactors using fixed carbon substrates (e.g., sugar). The process achieved biomass and lipid productivities of 0.5 and 0.27 g/L/h that were, respectively, over 250 and 670 times higher than those obtained from the photoautotrophic cultivation stage. The biomass oil content (over 60% w/DCW) following the two-stage process was predominantly monounsaturated fatty acids (~82%) and largely free of contaminating pigments that is more suitable for biodiesel production than photosynthetically generated lipid. Similar process performances were obtained using cassava hydrolysate as an alternative feedstock to glucose.

tert-Butyl 2-methyl-2-(4-methyl-benzo-yl)propanoate.

The title compound, C(16)H(22)O(3), is bent with a dihedral angle of 75.3 (1)° between the mean planes of the benzene ring and a group encompassing the ester functionality (O=C-O-C). In the crystal, the mol-ecules are linked into infinite chains held together by weak C-H⋯O hydrogen-bonded inter-actions between an H atom on the benzene ring of one mol-ecule and an O atom on the ketone functionality of an adjacent mol-ecule. The chains are arranged with neighbouring tert-butyl and dimethyl groups on adjacent chains exhibiting hydro-phobic stacking, with short C-H⋯H-C contacts (2.37 Å) between adjacent chains.

Single-mode tellurite glass holey fiber with extremely large mode area for infrared nonlinear applications.

We report the fabrication of a large mode area tellurite holey fiber from an extruded preform, with a mode area of 3000microm(2). Robust single-mode guidance at 1.55microm was confirmed by both optical measurement and numerical simulation. The propagation loss was measured as 2.9dB/m at 1.55microm. A broad and flat supercontinuum from 0.9 to 2.5microm with 6mW output was obtained with a 9cm length of this fiber.

Attenuation of interleukin-1beta by pulsed electromagnetic fields after traumatic brain injury.

Traumatic Brain Injury (TBI) is a major cause of morbidity and mortality in civilian and military populations. Interleukin-1beta (IL-1ß) is a pro-inflammatory cytokine with a key role in the inflammatory response following TBI and studies indicate that attenuation of this cytokine improves behavioral outcomes. Pulsed electromagnetic fields (PEMF) can reduce inflammation after soft tissue injuries in animals and humans. Therefore, we explored whether PEMF signals could alter the course of IL-1ß production in rats subjected to closed-head contusive weight-drop injuries (Marmarou method) and penetrating needle-stick brain injuries. Protein levels, measured by the Biorad assay, were not altered by injuries or PEMF treatment. In addition, we verified that IL-1ß levels in cerebrospinal fluid (CSF) were proportional to injury severity in the contusion model. Results demonstrate that PEMF treatment attenuated IL-1ß levels up to 10-fold in CSF within 6h after contusive injury and also significantly suppressed IL-1ß within 17-24h after penetrating injury. In contrast, no differences in IL-1ß were seen between PEMF-treated and control groups in brain homogenates. To the authors' knowledge, this is the first report of the use of PEMF to modulate an inflammatory cytokine after TBI. These results warrant further studies to assess the effects of PEMF on other inflammatory markers and functional outcomes.