Ligand-Enabled Cross-Coupling of C(sp³)–H Bonds with Arylsilanes

Pd­(II)-catalyzed cross-coupling of C­(sp³)–H bonds with organosilicon coupling partners has been achieved for the first time. The use of a newly developed quinoline-based ligand is essential for the cross-coupling reactions to proceed

Removal of Sulfonated Humic Acid through a Hybrid Electrocoagulation–Ultrafiltration Process

This study investigated the removal of sulfonated humic acid (SHA) from water through a hybrid electrocoagulation–ultrafiltration treatment process. The effects of major operating parameters including electrocoagulation time, current density, and initial pH on the electrocoagulation performance were evaluated. The increase in current density and operating time as well as decrease of pH improved the SHA removal efficiency. The operating conditions of electrocoagulation process were optimized through Box–Behnken design to maximize SHA removal. The optimum conditions for electrocoagulation included time of 7 min, current density of 10 mA/cm², and pH of 5. Effective SHA removal was further achieved in the hybrid electrocoagulation–ultrafiltration treatment process. The performances of three molecular weight cutoff membranes were examined. The results showed that the SHA removal efficiency increased with the increasing initial concentration of SHA and decreased with the increasing transmembrane pressure. The SHA removal efficiency was more than 95% by 5 kDa membrane. The SHA removal efficiency by different membranes from high to low in turn was: 5 kDa > 8 kDa > 10 kDa. The results will have significant implications for the treatment of complex drilling and hydraulic fracturing wastewater through electrocoagulation–ultrafiltration process

Amyloidosis, Synucleinopathy, and Prion Encephalopathy in a Neuropathic Lysosomal Storage Disease: The CNS-Biomarker Potential of Peripheral Blood

<div><p>Mucopolysaccharidosis (MPS) IIIB is a devastating neuropathic lysosomal storage disease with complex pathology. This study identifies molecular signatures in peripheral blood that may be relevant to MPS IIIB pathogenesis using a mouse model. Genome-wide gene expression microarrays on pooled RNAs showed dysregulation of 2,802 transcripts in blood from MPS IIIB mice, reflecting pathological complexity of MPS IIIB, encompassing virtually all previously reported and as yet unexplored disease aspects. Importantly, many of the dysregulated genes are reported to be tissue-specific. Further analyses of multiple genes linked to major pathways of neurodegeneration demonstrated a strong brain-blood correlation in amyloidosis and synucleinopathy in MPS IIIB. We also detected prion protein (Prnp) deposition in the CNS and Prnp dysregulation in the blood in MPS IIIB mice, suggesting the involvement of Prnp aggregation in neuropathology. Systemic delivery of trans-BBB-neurotropic rAAV9-hNAGLU vector mediated not only efficient restoration of functional <i>α-N</i>-acetylglucosaminidase and clearance of lysosomal storage pathology in the central nervous system (CNS) and periphery, but also the correction of impaired neurodegenerative molecular pathways in the brain and blood. Our data suggest that molecular changes in blood may reflect pathological status in the CNS and provide a useful tool for identifying potential CNS-specific biomarkers for MPS IIIB and possibly other neurological diseases.</p></div

Functional and disease association of blood transcriptional profile in MPS IIIB mice.

<p>Genome-wide gene expression microarrays were performed on pooled blood and brain RNA samples from 6 mo-old MPS IIIB mice and their wt littermates (n = 6/group, M:F = 1∶1). Genes of transcripts were identified by Ingenuity Pathway Analysis (IPA).</p>*<p>Genes associated with specific tissues according to enrichment analysis using Database for Annotation, Visualization and Integrated Discovery (DAVID); <b>FC>2:</b> fold change >2;</p>**<p>% of known genes.</p

Dysregulation of pathways involved in amyloidosis in the brain and blood in MPS IIIB mice and their response to rAAV9-hNAGLU gene delivery.

<p><b>a.</b> Total RNA from the brain (cortex), peripheral blood (PB) and/or representative control somatic tissues of 2 mo and/or 6 mo old wt, MPS IIIB mice, and MPS IIIB mice treated with an IV injection of rAAV9-CMV-hNAGLU (1×10¹³ vg/kg), were assayed by qRT-PCR (n = 9–12/group). Data: relative expression vs. wt. <b>b & c.</b> Brain tissue sections (4 µm) from 6 mo-old mice (n = 7) were assayed by IHC for Necab3. Necab3-positive calls/signals were stained brown (<b>b</b>) (red arrows). Necab3 staining intensity was quantitated using ImageJ (<b>c</b>). <b>d.</b> Whole cell proteins of brain cortical tissues from 6 mo-old mice were assayed by ELISA for pApp levels. <b>+/+:</b> wt mice; <b>−/−:</b> non-treated MPS IIIB mice; <b>AAV9:</b> rAAV9-treated MPS IIIB mice; CTX: cerebral cortex; DG: dentate gyrus of hippocampus. <b>*:</b> P<0.05 vs. wt; <b>#:</b> P<0.05 vs. AAV9-treated; <b>+:</b> P>0.05 vs. wt; <b>$:</b> P>0.05 vs.AAV9-treated. Scale bar: 50 µm.</p

Dysregulation in prion protein in the brain and blood in MPS IIIB mice and their response to rAAV9-hNAGLU gene delivery.

<p>Total RNA from the brain (cortex), peripheral blood (PB) and control somatic tissues of 6 mo old mice were assayed for Prnp by qRT-PCR (n = 9–12/group) (<b>a</b>). Data: relative expression vs. wt. Brain tissue sections (4 µm) from 6 mo-old mice (n = 7) were assayed for Prnp by immunohistochemistry (<b>b, c</b>). Prnp-positive signals were stained brown (<b>b</b>). Prnp staining intensity in PL was quantitated using ImageJ (<b>c</b>). <b>+/+:</b> wt mice; <b>−/−:</b> non-treated MPS IIIB mice; <b>AAV9:</b> rAAV9-treated MPS IIIB mice; <b>#1:</b> mouse with low Prnp IHC intensity; <b>#2:</b> mouse with high Prnp IHC intensity; <b>DG:</b> dentate gyrus of hippocampus. <b>PL:</b> polymoph layer of DG; <b>*:</b> P<0.05 vs. wt; <b>#:</b> P<0.05 vs. AAV9-treated; <b>+:</b> P>0.05 vs. wt; <b>$:</b> P>0.05 vs.AAV9-treated. Scale bar: 50 µm.</p

rAAV9-mediated restoration of NAGLU activity, correction of GAG storage and astrocytosis, and functional benefits MPS IIIB mice.

<p>4–6wk old MPS IIIB mice were treated with an IV injection of rAAV9-CMV-hNAGLU vector (1×10¹³ vg/kg). Mice were tested for behavior in Morris water maze at 5–5.5 mo old (n = 13) (<b>a</b>). Longevity studies are ongoing (n = 11) (<b>b</b>).Tissue analyses were performed at 6 mo of age. <b>c.</b> tissue NAGLU activity (no detectable NAGLU activity in tissues from non-treated MPS IIIB mice). <b>d.</b> Immunofluorescence (IF) for hNAGLU. Red fluorescence: hNAGLU-positive cells/signals. CTX: cerebral cortex; TH: thalamus; <b>BS:</b> brain stem; <b>Live:</b> liver; <b>Hrt:</b> heart. <b>Green arrows:</b> hNAGLU-positive neurons; <b>Yellow arrows:</b> hNAGLU positive vasculatures. <b>e.</b> tissue GAG contents; <b>f.</b> IF staining for LAMP-1. Red fluorescence: LAMP-1-positive calls/signals. g. IF staining for GFAP. Green fluorescence: GFAP-positive cells/signals. <b>*:</b> P<0.05 vs. WT; <b>#:</b> P<0.05 vs. AAV9-treated; <b>+:</b> P>0.05 vs. WT; ^∧: P>0.05 vs +/+ and AAV9-treated. Scale bar: 50 µm.</p

Direct C–H Functionalization of Pyridine via a Transient Activator Strategy: Synthesis of 2,6-Diarylpyridines

A Pd-catalyzed highly selective direct diarylation of pyridines has been developed using a transient activator strategy. Both (MeO)₂SO₂ and Cu₂O are required for this transformation. The in situ generated <i>N</i>-methylpyridinium salt can be arylated at both 2- and 6-positions under the cooperative Pd/Cu catalysis. A subsequent <i>N</i>-demethylation then gives the 2,6-diarylpyridines. This protocol provides a novel synthetic route for the symmetric 2,6-diarylpyridines