Comparative proteomic profiling reveals mechanisms for early spinal cord vulnerability in CLN1 disease

CLN1 disease is a fatal inherited neurodegenerative lysosomal storage disease of early childhood, caused by mutations in the CLN1 gene, which encodes the enzyme Palmitoyl protein thioesterase-1 (PPT-1). We recently found significant spinal pathology in Ppt1-deficient (Ppt1−/−) mice and human CLN1 disease that contributes to clinical outcome and precedes the onset of brain pathology. Here, we quantified this spinal pathology at 3 and 7 months of age revealing significant and progressive glial activation and vulnerability of spinal interneurons. Tandem mass tagged proteomic analysis of the spinal cord of Ppt1−/−and control mice at these timepoints revealed a significant neuroimmune response and changes in mitochondrial function, cell-signalling pathways and developmental processes. Comparing proteomic changes in the spinal cord and cortex at 3 months revealed many similarly affected processes, except the inflammatory response. These proteomic and pathological data from this largely unexplored region of the CNS may help explain the limited success of previous brain-directed therapies. These data also fundamentally change our understanding of the progressive, site-specific nature of CLN1 disease pathogenesis, and highlight the importance of the neuroimmune response. This should greatly impact our approach to the timing and targeting of future therapeutic trials for this and similar disorders

Search for CP-violating Neutrino Non-Standard Interactions with the NOvA Experiment

This Letter reports a search for charge-parity (CP) symmetry violating non-standard interactions (NSI) of neutrinos with matter using the NOvA Experiment, and examines their effects on the determination of the standard oscillation parameters. Data from $\nu_{\mu}(\bar{\nu}_{\mu})\rightarrow\nu_{\mu}(\bar{\nu}_{\mu})$ and $\nu_{\mu}(\bar{\nu}_{\mu})\rightarrow\nu_{e}(\bar{\nu}_{e})$ oscillation channels are used to measure the effect of the NSI parameters $\varepsilon_{e\mu}$ and $\varepsilon_{e\tau}$. With 90% C.L. the magnitudes of the NSI couplings are constrained to be $|\varepsilon_{e\mu}| \, \lesssim 0.3$ and $|\varepsilon_{e\tau}| \, \lesssim 0.4$. A degeneracy at $|\varepsilon_{e\tau}| \, \approx 1.8$ is reported, and we observe that the presence of NSI limits sensitivity to the standard CP phase $\delta_{\tiny\text{CP}}$

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo

Measurement of neutrino and antineutrino neutral-current quasielasticlike interactions on oxygen by detecting nuclear deexcitation γ rays

Neutrino- and antineutrino-oxygen neutral-current quasielastic-like interactions are measured at Super-Kamiokande using nuclear de-excitation $\gamma$-rays to identify signal-like interactions in data from a $14.94 \ (16.35)\times 10^{20}$protons-on-target exposure of the T2K neutrino (antineutrino) beam. The measured flux-averaged cross sections on oxygen nuclei are$\langle \sigma_{\nu {\rm -NCQE}} \rangle = 1.70 \pm 0.17 ({\rm stat.}) ^{+ {\rm 0.51}}_{- {\rm 0.38}} ({\rm syst.}) \times 10^{-38} \ {\rm cm^2/oxygen}$with a flux-averaged energy of 0.82 GeV and$\langle \sigma_{\bar{\nu} {\rm -NCQE}} \rangle = 0.98 \pm 0.16 ({\rm stat.}) ^{+ {\rm 0.26}}_{- {\rm 0.19}} ({\rm syst.}) \times 10^{-38} \ {\rm cm^2/oxygen}$ with a flux-averaged energy of 0.68 GeV, for neutrinos and antineutrinos, respectively. These results are the most precise to date, and the antineutrino result is the first cross section measurement of this channel. They are compared with various theoretical predictions. The impact on evaluation of backgrounds to searches for supernova relic neutrinos at present and future water Cherenkov detectors is also discussed

Measurements of the νμ\nu_{\mu} and νˉμ\bar{\nu}_{\mu}-induced Coherent Charged Pion Production Cross Sections on 12C^{12}C by the T2K experiment

We report an updated measurement of the $\nu_{\mu}$-induced, and the first measurement of the $\bar{\nu}_{\mu}$-induced coherent charged pion production cross section on $^{12}C$ nuclei in the T2K experiment. This is measured in a restricted region of the final-state phase space for which $p_{\mu,\pi} > 0.2$ GeV, $\cos(\theta_{\mu}) > 0.8$ and $\cos(\theta_{\pi}) > 0.6$, and at a mean (anti)neutrino energy of 0.85 GeV using the T2K near detector. The measured $\nu_{\mu}$ CC coherent pion production flux-averaged cross section on $^{12}C$ is $(2.98 \pm 0.37 (stat.) \pm 0.31 (syst.) \substack{ +0.49 \\ -0.00 } \mathrm{ (Q^2\,model)}) \times 10^{-40}~\mathrm{cm}^{2}$. The new measurement of the $\bar{\nu}_{\mu}$-induced cross section on $^{12}{C}$ is $(3.05 \pm 0.71 (stat.) \pm 0.39 (syst.) \substack{ +0.74 \\ -0.00 } \mathrm{(Q^2\,model)}) \times 10^{-40}~\mathrm{cm}^{2}$. The results are compatible with both the NEUT 5.4.0 Berger-Sehgal (2009) and GENIE 2.8.0 Rein-Sehgal (2007) model predictions

Overview of Current Drugs and Molecules in Development for Spinal Muscular Atrophy Therapy

The full text of this article can be found here: https://link.springer.com/article/10.1007/s40265-018-0868-

Search for electron antineutrino appearance in a long-baseline muon antineutrino beam

Electron antineutrino appearance is measured by the T2K experiment in an accelerator-produced antineutrino beam, using additional neutrino beam operation to constrain parameters of the Pontecorvo-Maki-Nakagawa-Sakata (PMNS) mixing matrix. T2K observes 15 candidate electron antineutrino events with a background expectation of 9.3 events. Including information from the kinematic distribution of observed events, the hypothesis of no electron antineutrino appearance is disfavored with a significance of 2.40σ and no discrepancy between data and PMNS predictions is found. A complementary analysis that introduces an additional free parameter which allows non-PMNS values of electron neutrino and antineutrino appearance also finds no discrepancy between data and PMNS predictions

Effect of sucralfate on components of mucosal barrier produced by cultured canine epithelial cells in vitro

The mucous gel maintains a neutral microclimate at the epithelial cell surface, which may play a role in both the prevention of gastroduodenal injury and the provision of an environment essential for epithelial restitution and regeneration after injury. Enhancement of the components of the mucous barrier by sucralfate may explain its therapeutic efficacy for upper gastrointestinal tract protection, repai, and healing. We studied the effect of sucralfate and its major soluble component, sucrose octasulfate (SOS), on the synthesis and release of gastric mucin and surface active phospholipid, utilizing an isolated canine gastric mucous cells in culture. We correlated these results with the effect of the agents on mucin synthesis and secretion utilizing explants of canine fundus in vitro . Sucralfate and SOS significantly stimulated phospholipid secretion by isolated canine mucous cells in culture (123% and 112% of control, respectively.) Indomethacin pretreatment siginificantly inhibited the effect of sucralfate, but not SOS, on the stimulation of phospholipid release. Administration of either sucralfate or SOS to the isolated canine mucous cells had no effect upon mucin synthesis or secretion using a sensitive immunoassay. Sucralfate and SOS did not stimulate mucin release in the canine explants; sucralfate significantly stimulated the synthesis of mucin, but only to 108% of that observed in untreated explants. No increase in PGE 2 release was observed after sucralfate or SOS exposure to the isolated canine mucous cells. Our results suggest sucralfate affects the mucus barrier largely in a qualitative manner. No increase in mucin secretion or major effect on synthesis was notd, although a significant increase in surface active phospholipid release was observed. The lack of dose dependency of this effect, along with the results of the PGE 2 assay, suggests the drug may act through a non-receptor-mediated mechanism to perturb the cell membrane and release surface active phospholipid. The enhancement of phospholipid release by sucralfate to augment the barrier function of gastric mucus may, in concert with other effects of the drug, strrengthen mucosal barrier function.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44415/1/10620_2005_Article_BF01308079.pd

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist