Removal of gelatin from live vaccines and DTaP—an ultimate solution for vaccine-related gelatin allergy

From the early 1990s infants started to receive acellular pertussis vaccine combined with diphtheria and tetanus toxoids (DTaP) before live vaccines such as measles, rubella, and mumps vaccines, which contained gelatin as a stabilizer. Then, an increasing number of cases of anaphylactic/allergic reactions to those live vaccines were reported. Almost all these cases had a previous history of receiving three or four doses of DTaP containing gelatin.Anaphylactic/allergic reactions to live measles vaccine were analyzed using information obtained from the Reporting System, a retrospective study, as well as from the Monitoring System, a prospective study. Dramatic decreases in anaphylactic/allergic reactions to live measles vaccines were observed immediately after each manufacturer marketed gelatin-free or gelatin (hypo-allergic)-containing live measles vaccine, and since the end of 1998 reports on anaphylactic/allergic reactions to live measles vaccine have almost ceased.     

Anti-oligosaccharide antibodies as tools for studying sulfated sialoglycoconjugate ligands for siglecs and selectins

Several sulfated sialoglycoconjugates have recently been shown to serve as ligands for selectins and siglecs. For instance, α2→3 sialylated 6-sulfo-Lewis x was found to serve as a ligand for selectins on skin-homing helper memory T cells, and α2→6 sialylated 6-sulfo-LacNAc to be a preferred ligand for CD22/siglec-2 on human naïve B cells. Monoclonal antibodies specific to sulfated sialoglycoconjugates are effective tools to dissect these ligands on minor subsets of human leukocytes.     

Immature Pacific bluefin tuna, <Emphasis Type="Italic">Thunnus orientalis</Emphasis>, utilizes cold waters in the Subarctic Frontal Zone for trans-Pacific migration

The habitat and movements of a Pacific bluefin tuna were investigated by reanalyzing archival tag data with sea surface temperature data. During its trans-Pacific migration to the eastern Pacific, the fish took a direct path and primarily utilized waters, in the Subarctic Frontal Zone (SFZ). Mean ambient temperature during the trans-Pacific migration was 14.5 ± 2.9 (°C ± SD), which is significantly colder than the waters typically inhabited by bluefin tuna in their primary feeding grounds in the western and eastern Pacific (17.6 ± 2.1). The fish moved rapidly through the colder water, and the heat produced during swimming and the thermoconservation ability of bluefin tuna likely enabled it to migrate through the cold waters of the SFZ.     

A new species of Haborophocoena, an Early Pliocene phocoenid cetacean from Hokkaido, Japan

A new species of phocoenid cetacean Haborophocoena , collected from the Early Pliocene Embetsu Formation, in the close vicinity to the site where the holotype of the type species of the genus Haborophocoena was retrieved, improves our knowledge of the anatomy of this cetacean. The new species, represented by a skull, lacking distal half of the rostrum, ear bones, and teeth, is significantly smaller than, but morphologically similar to, the type species Haborophocoena toyoshimai Ichishima and Kimura 2005 . This new record of Haborophocoena confirms the veracity of the genus Haborophocoena as a biological entity, contributes to understanding the interspecific variation, and suggests that the genus diversified in the northwestern Pacific of early Pliocene time. The adult-like degree of ossification in this small skull precludes it from being a juvenile of Haborophocoena toyoshimai . Autapomorphies of Haborophocoena minutus include narrow premaxilla on the dorsal surface of the rostrum, the anterior position of the premaxillary foramen, and a distinct ridge dividing a fossa on the lateral face of the base of the zygomatic process into the dorsal and the ventral halves, the zygomatic process rectangular in lateral profile, and its small size, which is the most compelling feature, making it a distinct species.     

Discovery and biological profile of isoindolinone derivatives as novel metabotropic glutamate receptor 1 antagonists: A potential treatment for psychotic disorders

We describe here the discovery and biological profile of a series of isoindolinone derivatives as developed mGluR1 antagonists. Our combined strategy of rapid parallel synthesis and conventional medicinal optimization successfully led to N-cyclopropyl 22 and N-isopropyl isoindolinone analogs 21 and 23 with improved in vivo DMPK profiles. Moreover the most advanced analog 23 showed an oral antipsychotic-like effect at a dose of 1 mg/kg in an animal model.     

New Rev-export inhibitor from Alpinia galanga and structure–activity relationship

Bioassay-guided separation by use of the fission yeast expressing NES of Rev, an HIV-1 viral regulatory protein, disclosed 1′-acetoxychavicol acetate (ACA, 1) as a new inhibitor for nuclear export of Rev from the roots of Alpinia galanga. Both analysis for mechanism of action with biotinylated probe (2) and several synthesized analogs established crucial portions in 1 for Rev-export inhibitory activity.     

The synthesis and structure–activity relationship of substituted N-phenyl anthranilic acid analogs as amyloid aggregation inhibitors

It is believed that β-amyloid aggregation is an important event in the development of Alzheimer’s disease. In the course of our studies to identify β-amyloid aggregation inhibitors, a series of N-phenyl anthranilic acid analogs were synthesized and studied for β-amyloid inhibition activity. The synthesis, structure–activity relationship, and in vivo activity of these analogs are discussed.     

Acetyl-Ile-Gly-Leu protects neurons from Aβ1–42 induced toxicity in vitro and in V337M human tau-expressing mice

AimsWe previously reported that the neurotoxicity of amyloid β protein (Aβ_1–42, 10 nM) was blocked by an Aβ-derived tripeptide, Aβ_32–34 (Ile-Gly-Leu, IGL), suggesting that IGL may be a lead compound in the design of Aβ antagonists. In the present study, three stable forms of IGL peptide with acetylation of its N-terminal and/or amidation of its C-terminal (acetyl-IGL, IGL-NH₂ and acetyl-IGL-NH₂) were synthesized and examined for their effects on Aβ-induced neurotoxicity.Main methodsPhosphatidylinositol 4-kinase type II (PI4KII) activity was measured using recombinant human PI4KIIα kinase and cell viability was assessed in primary cultured hippocampal neurons. To test effects in vivo, 1.5 μl of 100 nM Aβ and/or 100 nM acetyl-IGL was injected into the hippocampal CA1 region of right hemisphere in transgenic mice expressing V337M human tau protein. Four weeks later, behavior performance in the Morris water maze was tested and after another 2 weeks, sections of brain were prepared for immunohistochemistry.Key findingsAmong the three modified tripeptides, acetyl-IGL attenuated the Aβ-induced inhibition of PI4KII activity as well as enhancement of glutamate neurotoxicity in primary cultured rat hippocampal neurons. Injection of Aβ into the hippocampus of mice impaired spatial memory and increased the number of degenerating neurons in bilateral hippocampal regions. Co-injection of acetyl-IGL prevented the learning impairment as well as the neuronal degeneration induced by Aβ.SignificanceThese results suggest that a modified tripeptide, acetyl-IGL, may be effective in the treatment of Alzheimer's disease.     

Effect of Pin1 or Microtubule Binding on Dephosphorylation of FTDP-17 Mutant Tau

Neurodegenerative tauopathies, including Alzheimer disease, are characterized by abnormal hyperphosphorylation of the microtubule-associated protein Tau. One group of tauopathies, known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), is directly associated with mutations of the gene tau. However, it is unknown why mutant Tau is highly phosphorylated in the patient brain. In contrast to in vivo high phosphorylation, FTDP-17 Tau is phosphorylated less than wild-type Tau in vitro. Because phosphorylation is a balance between kinase and phosphatase activities, we investigated dephosphorylation of mutant Tau proteins, P301L and R406W. Tau phosphorylated by Cdk5-p25 was dephosphorylated by protein phosphatases in rat brain extracts. Compared with wild-type Tau, R406W was dephosphorylated faster and P301L slower. The two-dimensional phosphopeptide map analysis suggested that faster dephosphorylation of R406W was due to a lack of phosphorylation at Ser-404, which is relatively resistant to dephosphorylation. We studied the effect of the peptidyl-prolyl isomerase Pin1 or microtubule binding on dephosphorylation of wild-type Tau, P301L, and R406W in vitro. Pin1 catalyzes the cis/trans isomerization of phospho-Ser/Thr-Pro sequences in a subset of proteins. Dephosphorylation of wild-type Tau was reduced in brain extracts of Pin1-knockout mice, and this reduction was not observed with P301L and R406W. On the other hand, binding to microtubules almost abolished dephosphorylation of wild-type and mutant Tau proteins. These results demonstrate that mutation of Tau and its association with microtubules may change the conformation of Tau, thereby suppressing dephosphorylation and potentially contributing to the etiology of tauopathies.One of hallmarks of Alzheimer disease (AD)³ pathology is neurofibrillary tangles, which are composed of paired helical filaments (PHFs), aggregates of the abnormally phosphorylated microtubule-associated protein Tau. Intracellular inclusions comprising Tau are also found in several other neurodegenerative diseases, including Pick disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), collectively called tauopathies (1–3). Identification of Tau as a causative gene of the inherited tauopathy FTDP-17 reveals that Tau mutation is sufficient to cause disease (4–6). However, the impact Tau mutations have on neurodegeneration remains unknown.Tau proteins in inclusions are hyperphosphorylated, and extensive studies have identified the phosphorylation sites; for example, more than 20 sites have been identified in PHF-Tau obtained from AD brains (7, 8). Tau can be phosphorylated by a variety of protein kinases, including glycogen synthase kinase 3β (GSK3β), cyclin-dependent kinase 5 (Cdk5), mitogen-activated protein kinase, cAMP-dependent protein kinase (PKA), microtubule affinity regulating kinase, and others (9–11). Tau is predominantly phosphorylated on the Ser or Thr residue in Ser/Thr-Pro sequences, suggesting the involvement of proline-directed protein kinases such as GSK3β and Cdk5 in hyperphosphorylation. A critical question is how mutations in Tau induce hyperphosphorylation in brain (12). Early phosphorylation experiments in vitro and in cultured cells have shown that mutant Tau is less phosphorylated than wild-type (WT) Tau (13–18). However, two later studies demonstrated higher phosphorylation of mutant Tau using brain extracts as a source of protein kinases in the presence of protein phosphatase inhibitor okadaic acid (19) or in immortalized cortical cells (20). However, it is not fully understood how mutant Tau becomes highly phosphorylated in vivo.Tau hyperphosphorylation could also be attributed to reduced dephosphorylation activity. Tau is dephosphorylated in vitro by any of the major four classes of protein phosphatases, PP1, PP2A, PP2B, and PP2C, but PP2A is thought to be the major protein phosphatase that regulates Tau phosphorylation state in brains (21–23). PP2A activity reportedly is decreased in AD brain (24–26), and highly phosphorylated Tau in PHF is relatively resistant to dephosphorylation by PP2A (27). Few studies have been done on dephosphorylation of mutant Tau, however, and thus the mechanism remains unclear. One putative factor involved in mutant Tau dephosphorylation is the peptidyl-prolyl isomerase Pin1. Pin1 catalyzes the cis/trans isomerization of phospho-Ser/Thr-Pro sequences in a subset of proteins (28, 29). Pin1 is involved in AD pathogenesis as shown by the fact that it is found in neurofibrillary tangles and that Tau is hyperphosphorylated in Pin1-deficient mouse brains (30). Pin1 is indicated to facilitate Tau dephosphorylation via PP2A by binding to the phospho-Thr-231-Pro or phospho-Thr-212-Pro site (31–33). The effect of Pin1 on the stability of mutant Tau was recently reported (34), but a detailed analysis of Pin1 action on mutant Tau has not been reported. Another possible factor affecting dephosphorylation of mutant Tau is the binding to microtubules. We previously showed that phosphorylation of Tau is stimulated upon binding to microtubules (35). We thus hypothesized that binding to microtubules may also affect the extent of Tau dephosphorylation.Here, we examined the effects of Pin1 and binding to microtubules on dephosphorylation of WT and FTDP-17 mutant (P301L and R406W) Tau proteins that had been phosphorylated by Cdk5-p25 or Cdk5-p35. P301L and R406W are two distinct types of FTDP-17 mutants that have been studied well. We show for the first time how the regulation of Tau dephosphorylation can contribute to the observed Tau hyperphosphorylation in tauopathies.