Neural-specific ablation of the scaffold protein JSAP1 in mice causes neonatal death

We previously identified c-Jun NH₂-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JNK-interacting protein 3) as a scaffolding factor for JNK intracellular signaling pathways. Targeted gene-disruption studies have shown that JSAP1-null mice are unable to breathe and die shortly after birth. Although neural defects might be responsible for their death, there has been no convincing evidence for this. Here we first generated genetically engineered mice carrying a loxP-flanked (floxed) jsap1 gene. To evaluate the validity of this deletion as a jsap1 conditional knockout (KO), we created mice in which the same exon was deleted in all cell lineages, and compared their phenotypes with those of the jsap1 conventional KO mice reported previously. The two KO lines showed indistinguishable phenotypes, i.e., neonatal death and morphological defects in the telencephalon, indicating that the conditional deletion was a true null mutation. We then introduced the floxed jsap1 deletion mutant specifically into the neural lineage, and found that the jsap1 conditional KO mice showed essentially the same phenotypes as the JSAP1-null mice. These results strongly suggest that the neonatal death of jsap1-deficient mice is caused by defects in the nervous system.     

Structural and biological constraints on diversity of regions immediately upstream of cleavage sites in calicivirus precursor proteins

To address the regulation and evolution of precursor protein cleavability in caliciviruses, we examined constraints on diversity of upstream regions of calicivirus precursor cleavage sites. We performed alanine scanning and supplementary mutagenesis of amino acids at P1, P2, P3, and P4 sites using four viruses representing the four major genera of the family Caliciviridae. This study complements previous mutagenesis studies and shows strong restrictions in mutations at the P1 and P4 sites for effective cleavage reactions. By contrast, such restrictions were less frequently observed at the P2 and P3 sites. Shannon entropy analysis of the reported sequences showed that the P2, P3, and P4 sites allow variations in amino acid size within a calicivirus genus whereas the P1 sites do not. Notably, the human sapovirus precursor protein exceptionally retains a basic rather than aromatic amino acid at the P4 site of the NS4/NS5 cleavage site in reported strains, and a substitution from basic to aromatic amino acid significantly enhanced cleavability at this site. Taken together, these data suggest the existence of (i) structural constraints on the P1 site that restrict size changes within each calicivirus genus, (ii) plastic substrate surfaces that accommodate size variation at the P2, P3, and P4 sites and modulate their own cleavabilities, and (iii) biological constraints on the P4 site that maintain the lower cleavability of the NS4/NS5 site in sapovirus.     

Intravenous ulinastatin therapy for Stevens-Johnson syndrome and toxic epidermal necrolysis in pediatric patients. Three case reports

BACKGROUND: More effective therapy is needed for the treatment of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The clinical efficacy of intravenous ulinastatin therapy was investigated in 3 Japanese pediatric patients with SJS or TEN. METHODS: Ulinastatin was given to 1 pediatric SJS patient and 2 pediatric TEN patients within 7 days (patient 1; SJS), 6 days (patient 2; TEN), or 4 days (patient 3; TEN) after the onset of the skin rash. Ulinastatin was administered intravenously at a dose of 7,500 U/kg/day (maximum dose: 300,000 U/day). No corticosteroids were given. After the skin lesions resolved, the ulinastatin dose was reduced to between 2,500 and 5,000 U/kg/day as maintenance therapy and then the drug was withdrawn. RESULTS: Erythema, fatigue, and fever improved within 12-36 h of starting the ulinastatin infusion, and the skin lesions resolved completely after 4-7 days of ulinastatin therapy. None of the patients had cutaneous or ocular sequelae. No patient developed secondary infection or relapse and ulinastatin therapy caused no side effects. CONCLUSION: Ulinastatin dramatically reduced the febrile period with no adverse effects and was very safe in this study. Ulinastatin appears to be a useful and effective therapy for controlling SJS and TEN without sequelae.     

中文大学生版Buss-Perry攻击性量表的修订与信效度分析

目的:引进Buss-Perry攻击性量表(BPAQ),并在大学生群体中进行修订,用来测量我国大学生的攻击性水平.方法:在不同行政区域的9所综合型大学抽取1722名在校大学生.对样本编号后,奇数组(n =864)被用于探索性因素分析以确认因子结构;偶数组(n=858)被用于对所得维度进行验证性因素分析.用大学生社会技能量表(ChUSSI)和羞涩量表(RCBS)为效标.抽取其中一所大学的165名学生于初评后2周进行重测.结果:通过探索性因素分析,得到由敌意、身体攻击、冲动、易怒性4个分量表(共22个项目)构成的中文大学生版Buss-Perry攻击性量表(CC-BPAQ);验证性因素分析显示数据拟合良好(GFI=0.917,AGFI=0.896,CFI=0.899,RMSEA=0.059);CC-BPAQ的敌意、身体攻击和易怒性分量表得分与ChUSSI得分呈负相关(r=-0.23、-0.19、-0.20,均P＜0.01),CC-BPAQ的4个分量表得分均与RCBS得分呈正相关(r=0.45、0.21、0.11、0.32,均P＜0.01).总量表的内部一致性Cronbach α系数为0.89,4个分量表的α系数为0.73 ～0.85;总量表的重测信度为0.91,4个分量表的重测信度为0.75 ～0.80.结论:修订后的中文大学生版Buss-Perry攻击性量表具有良好的信度和效度,可以用于大学生的攻击性测量.     

High prevalence of equine-like G3P[8] rotavirus in children and adults with acute gastroenteritis in Thailand

Group A rotavirus (RVA) is a major cause of acute gastroenteritis in infants and young children worldwide. This study aims to clarify the distribution of G/P types and genetic characteristics of RVAs circulating in Thailand. Between January 2014 and September 2016, 1867 stool specimens were collected from children and adults with acute gastroenteritis in six provinces in Thailand. RVAs were detected in 514/1867 (27.5%) stool specimens. G1P[8] (44.7%) was the most predominant genotype, followed by G3P[8] (33.7%), G2P[4] (11.5%), G8P[8] (7.0%), and G9P[8] (1.3%). Unusual G3P[9] (0.8%), G3P[10] (0.4%), G4P[6] (0.4%), and G10P[14] (0.2%) were also detected at low frequencies. The predominant genotype, G1P[8] (64.4%), in 2014 decreased to 6.1% in 2016. In contrast, the frequency of G3P[8] markedly increased from 5.5% in 2014 to 65.3% in 2015 and 89.8% in 2016. On polyacrylamide gel electrophoresis, most (135/140; 96.4%) of the G3P[8] strains exhibited a short RNA profile. Successful determination of the nucleotide sequences of the VP7 genes of 98 G3P[8] strains with a short RNA profile showed that they are all equine-like G3P[8] strains. On phylogenetic analysis of genome segments of two representative Thai equine-like G3P[8] strains, it was noteworthy that they possessed distinct NSP4 genes, one bovine-like and the other human-like. Thus, we found that characteristic equine-like G3P[8] strains with a short RNA electropherotype are becoming highly prevalent in children and adults in Thailand.     

Metastatic profiling of HER2-positive breast cancer cell lines in xenograft models

Most studies on breast cancer metastasis have been performed using triple-negative breast cancer cells; thus, subtype-dependent metastatic ability of breast cancer is poorly understood. In this research, we performed intravenous injection (IVI) and intra-caudal arterial injections using nine human epidermal growth factor receptor-2 (HER2)-positive breast cancer cell lines for evaluating their metastatic abilities. Our results showed that MDA-MB-453, UACC-893, and HCC-202 had strong bone metastatic abilities, whereas HCC-2218 and HCC-1419 did not show bone metastasis. HER2-positive cell lines could hardly metastasize to the lung through IVI. From the genomic analysis, gene signatures were extracted according to the breast cancer subtypes and their metastatic preferences. The UACC-893 cell line was identified as a useful model for the metastasis study of HER2-positive breast cancer. Combined with our previous result on brain metastasis ability, we provide a characteristic metastasis profile of HER2-positive breast cancer cell lines in this study.

     

Partial Trisomy 9p with Clinical Symptoms Resembling Interferonopathies

Journal of Clinical Immunology -     

The PPARgamma ligand, 15-Deoxy-Delta12,14-PGJ2, regulates apoptosis-related protein expression in cholangio cell carcinoma cells

PPARgamma is known to induce apoptosis in malignant tumor cells, but the mechanism of this induction is not well understood. We investigated induction of apoptosis with 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a PPARgamma ligand, in cholangio cell carcinoma (CCC) cells (RBE, ETK-1 or HuCCT-1). Apoptosis was induced in RBE and ETK-1 cells with 15d-PGJ2, but not in HuCCT-1 cells, although PPARgamma was expressed in all CCC cells. Apoptosis-related proteins were also expressed, including FLIP, bclx, Apaf-1 and XIAP, but expression levels differed among the three cell lines. RBE cells treated with 15d-PGJ2 showed caspase activation, and it appeared that PPARgamma-induced apoptosis was dependent on caspase activation. However, neither ETK-1 nor HuCCT-1 cells showed significant activation of caspase-8 or -3 with 15d-PGJ2 treatment, raising the possibility of a caspase-independent apoptosis induction pathway. XIAP was down-regulated by 15d-PGJ2 in all three CCC cell lines. Therefore, 15d-PGJ2 induces apoptosis in CCC cells via caspase-dependent or independent pathways. 15d-PGJ2 may also induce down-regulation of XIAP and may promote caspase cascade activation through TNF-family receptor signaling pathways.     

Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes

In order to evaluate the contribution of FBN1, FBN2, TGFBR1, and TGFBR2 mutations to the Marfan syndrome (MFS) phenotype, the four genes were analyzed by direct sequencing in 49 patients with MFS or suspected MFS as a cohort study. A total of 27 FBN1 mutations (22 novel) in 27 patients (55%, 27/49), 1 novel TGFBR1 mutation in 1 (2%, 1/49), and 2 recurrent TGFBR2 mutations in 2 (4%, 2/49) were identified. No FBN2 mutation was found. Three patients with either TGFBR1 or TGFBR2 abnormality did not fulfill the Ghent criteria, but expressed some overlapping features of MFS and Loeys-Dietz syndrome (LDS). In the remaining 19 patients, either of the genes did not show any abnormalities. This study indicated that FBN1 mutations were predominant in MFS but TGFBRs defects may account for approximately 5-10% of patients with the syndrome.