Flexible Ion‐Conducting Composite Membranes for Lithium Batteries

The use of metallic lithium anodes enables higher energy density and higher specific capacity Li‐based batteries. However, it is essential to suppress lithium dendrite growth during electrodeposition. Li‐ion‐conducting ceramics (LICC) can mechanically suppress dendritic growth but are too fragile and also have low Li‐ion conductivity. Here, a simple, versatile, and scalable procedure for fabricating flexible Li‐ion‐conducting composite membranes composed of a single layer of LICC particles firmly embedded in a polymer matrix with their top and bottom surfaces exposed to allow for ionic transport is described. The membranes are thin (<100 μm) and possess high Li‐ion conductance at thicknesses where LICC disks are mechanically unstable. It is demonstrated that these membranes suppress Li dendrite growth even when the shear modulus of the matrix is lower than that of lithium. It is anticipated that these membranes enable the use of metallic lithium anodes in conventional and solid‐state Li‐ion batteries as well as in future Li? S and Li? O₂ batteries.     

Unavoidable Human Errors of Tumor Size Measurement during Specimen Attachment after Endoscopic Resection: A Clinical Prospective Study

Objective

Objective evaluation of resected specimen and tumor size is critical because the tumor diameter after endoscopic submucosal dissection affects therapeutic strategies. In this study, we investigated whether the true tumor diameter of gastrointestinal cancer specimens measured by flexible endoscopy is subjective by testing whether the specimen is correctly attached to the specimen board after endoscopic submucosal dissection resection and whether the size differs depending on the endoscopist who attached the specimen.

Methods

Seventy-two patients diagnosed with early gastric cancer who satisfied the endoscopic submucosal dissection expanded-indication guideline were enrolled. Three endoscopists were randomly selected before every endoscopic submucosal dissection. Each endoscopist separately attached the same resected specimen, measured the maximum resection diameter and tumor size, and removed the lesion from the attachment board.

Results

The resected specimen diameters of the 3 endoscopists were 44.5±13.9 mm (95% Confidence Interval (CI): 23–67), 37.4±12.0 mm (95% CI: 18–60), and 41.1±13.3 mm (95% CI: 20–63) mm. Comparison among 3 groups (Kruskal Wallis H- test), there were significant differences (H = 6.397, P = 0.040), and recorded tumor sizes were 38.3±13.1 mm (95% CI: 16–67), 31.1±11.2 mm (95% CI: 12.5–53.3), and 34.8±12.8 (95% CI: 11.5–62.3) mm. Comparison among 3 groups, there were significant differences (H = 6.917, P = 0.031).

Conclusions

Human errors regarding the size of attached resected specimens are unavoidable, but it cannot be ignored because it affects the patient’s additional treatment and/or surgical intervention. We must develop a more precise methodology to obtain accurate tumor size.

Trial Registration

University hospital Medical Information Network UMIN No. 000012915     

Increase in Ultrasonic Intensity of Blood Speckle across Moderate Coronary Artery Stenosis Is an Independent Predictor of Functional Coronary Artery Stenosis Measured by Fractional Flow Reserve: Pilot Study

Background and Aims

The degree of coronary artery stenosis should be assessed both anatomically and functionally. We observed that the intensity of blood speckle (IBS) on intravascular ultrasound (IVUS) is low proximal to a coronary artery stenosis, and high distal to the stenosis. We defined step-up IBS as the distal minus the proximal IBS, and speculated that this new parameter could be used for the functional evaluation of stenosis on IVUS. The aims of this study were to assess the relationships between step-up IBS and factors that affect coronary blood flow, and between step-up IBS and fractional flow reserve (FFR).

Methods and Results

This study enrolled 36 consecutive patients with angina who had a single moderate stenosis in the left anterior descending artery. All patients were evaluated by integrated backscatter IVUS and intracoronary pressure measurements. FFR was calculated from measurements using a coronary pressure wire during hyperemia. Conventional gray-scale IVUS images were recorded, and integrated backscatter was measured in three cross-sectional slices proximal and distal to the stenosis. Step-up IBS was calculated as (mean distal integrated backscatter value) − (mean proximal integrated backscatter value). Stepwise multiple linear regression analysis showed that the heart rate (r = 0.45, P = 0.005), ejection fraction (r = −0.39, P = 0.01), and hemoglobin level (r = −0.32, P = 0.04) were independently correlated with step-up IBS, whereas proximal and distal IBS were not associated with these factors. There was a strong inverse correlation between step-up IBS and FFR (r = −0.84, P < 0.001), which remained significant on stepwise multiple linear regression analysis.

Conclusions

The newly defined parameter of step-up IBS is potentially useful for the functional assessment of coronary artery stenosis.     

Determining important regulatory relations of amino acids from dynamic network analysis of plasma amino acids

The changes in the concentrations of plasma amino acids do not always follow the flow-based metabolic pathway network. We have previously shown that there is a control-based network structure among plasma amino acids besides the metabolic pathway map. Based on this network structure, in this study, we performed dynamic analysis using time-course data of the plasma samples of rats fed single essential amino acid deficient diet. Using S-system model (conceptual mathematical model represented by power-law formalism), we inferred the dynamic network structure which reproduces the actual time-courses within the error allowance of 13.17%. By performing sensitivity analysis, three of the most dominant relations in this network were selected; the control paths from leucine to valine, from methionine to threonine, and from leucine to isoleucine. This result is in good agreement with the biological knowledge regarding branched-chain amino acids, and suggests the biological importance of the effect from methionine to threonine.     

Protein kinase Cdelta plays a non-redundant role in insulin secretion in pancreatic beta cells

Protein kinase C (PKC) is considered to modulate glucose-stimulated insulin secretion. Pancreatic beta cells express multiple isoforms of PKCs; however, the role of each isoform in glucose-stimulated insulin secretion remains controversial. In this study we investigated the role of PKCdelta, a major isoform expressed in pancreatic beta cells on beta cell function. Here, we showed that PKCdelta null mice manifested glucose intolerance with impaired insulin secretion. Insulin tolerance test showed no decrease in insulin sensitivity in PKCdelta null mice. Studies using islets isolated from these mice demonstrated decreased glucose- and KCl-stimulated insulin secretion. Perifusion studies indicated that mainly the second phase of insulin secretion was decreased. On the other hand, glucose-induced influx of Ca2+ into beta cells was not altered. Immunohistochemistry using total internal reflection fluorescence microscopy and electron microscopic analysis showed an increased number of insulin granules close to the plasma membrane in beta cells of PKCdelta null mice. Although PKC is thought to phosphorylate Munc18-1 and facilitate soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors complex formation, the phosphorylation of Munc18-1 by glucose stimulation was decreased in islets of PKCdelta null mice. We conclude that PKCdelta plays a non-redundant role in glucose-stimulated insulin secretion. The impaired insulin secretion in PKCdelta null mice is associated with reduced phosphorylation of Munc18-1.     

Migration behaviour and pathogenesis of five ascarid nematode species in the Mongolian gerbil Meriones unguiculatus

To understand the characteristic features of the Mongolian gerbil, Meriones unguiculatus, as an animal model of ascarid infections, the migration behaviour and pathogenesis of larvae were investigated in experimentally infected gerbils. Embryonated eggs from each of Toxocara canis, Baylisascaris procyonis, B. transfuga, Ascaris suum, and A. lumbricoides were orally inoculated into gerbils and larvae were recovered from various organs at designated periods. In T. canis-infected gerbils, larvae were present in the liver 3 days after infection and in the skeletal muscle and brain via the heart and lungs at a similar rate. In B. procyonis- and B. transfuga-infected gerbils, larvae were present in the lungs within 24 h after infection, with some having reached the brain by that time. After 24 h, larvae of B. procyonis tended to accumulate in the brain, while those of B. transfuga accumulated in skeletal muscles. In A. suum- and A. lumbricoides-infected gerbils, larvae remained in the liver on day 5 post-infection and elicited pulmonary haemorrhagic lesions, which disappeared 7 days after initial infection. Thereafter, no larvae of any type were recovered. Ocular manifestations were frequently observed in T. canis- and B. procyonis infected gerbils, but were rare in B. transfuga-infected gerbils. In the cases of A. suum and A. lumbricoides, migration to the central nervous system and eyes was extremely rare, and larvae had disappeared by 2 weeks post-infection. Fatal neurological disturbances were observed in B. procyonis-infected gerbils, whereas irreversible non-fatal neurological symptoms were observed in the case of B. transfuga.     

Further studies on hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors toward improved replicon cell activities: benzimidazole and structurally related compounds bearing the 2-morpholinophenyl moiety

Following the discovery of JTK-109 (1) as a potent inhibitor of hepatitis C virus NS5B RNA-dependent RNA polymerase, [(a) Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.; Yata, S.; Ando, I.; Komatsu, M.; Ikeda, S.; Hashimoto, H. J. Med. Chem.2006, 49, 4721. (b) Hashimoto, H.; Mizutani, K.; Yoshida, A. Int. Patent Appl. WO 01/47883, 2001.] further studies toward the improvement of the cellular potency have been performed. A greater than 40-fold improvement was achieved through replacing the biphenyl moiety with a 2-morpholinophenyl group and the benzimidazole ring with the tetracyclic scaffold to afford compound 7 with an excellent replicon potency (EC(50)=7.6 nM).     

Blocking neddylation elicits antiviral effect against hepatitis B virus replication

Molecular Biology Reports - Hepatitis B Virus (HBV) is the most common cause of chronic liver disease worldwide. The mechanisms that regulate HBV viral replication remain poorly defined. Here, we...     

Mammalian Bcnt/Cfdp1, a potential epigenetic factor characterized by an acidic stretch in the disordered N-terminal and Ser250 phosphorylation in the conserved C-terminal regions

The BCNT (Bucentaur) superfamily is classified by an uncharacteristic conserved sequence of ∼80 amino acids (aa) at the C-terminus, BCNT-C (the conserved C-terminal region of Bcnt/Cfdp1). Whereas the yeast Swc5 and Drosophila Yeti homologues play crucial roles in chromatin remodelling organization, mammalian Bcnt/Cfdp1 (craniofacial developmental protein 1) remains poorly understood. The protein, which lacks cysteine, is largely disordered and comprises an acidic N-terminal region, a lysine/glutamic acid/proline-rich 40 aa sequence and BCNT-C. It shows complex mobility on SDS/PAGE at ∼50 kDa, whereas its calculated molecular mass is ∼33 kDa. To characterize this mobility discrepancy and the effects of post-translational modifications (PTMs), we expressed various deleted His–Bcnt in E. coli and HEK cells and found that an acidic stretch in the N-terminal region is a main cause of the gel shift. Exogenous BCNT/CFDP1 constitutively expressed in HEK clones appears as a doublet at 49 and 47 kDa, slower than the protein expressed in Escherichia coli but faster than the endogenous protein on SDS/PAGE. Among seven in vivo phosphorylation sites, Ser²⁵⁰, which resides in a region between disordered and ordered regions in BCNT-C, is heavily phosphorylated and detected predominantly in the 49 kDa band. Together with experiments involving treatment with phosphatases and Ser²⁵⁰ substitutions, the results indicate that the complex behaviour of Bcnt/Cfdp1 on SDS/PAGE is caused mainly by an acidic stretch in the N-terminal region and Ser²⁵⁰ phosphorylation in BCNT-C. Furthermore, Bcnt/Cfdp1 is acetylated in vitro by CREB-binding protein (CBP) and four lysine residues including Lys²⁶⁸ in BCNT-C are also acetylated in vivo, revealing a protein regulated at multiple levels.