Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice

Rheumatoid arthritis (RA), which afflicts about 1% of the world population, is a chronic systemic inflammatory disease of unknown aetiology that primarily affects the synovial membranes of multiple joints. Although CD4(+) T cells seem to be the prime mediators of RA, it remains unclear how arthritogenic CD4(+) T cells are generated and activated. Given that highly self-reactive T-cell clones are deleted during normal T-cell development in the thymus, abnormality in T-cell selection has been suspected as one cause of autoimmune disease. Here we show that a spontaneous point mutation of the gene encoding an SH2 domain of ZAP-70, a key signal transduction molecule in T cells, causes chronic autoimmune arthritis in mice that resembles human RA in many aspects. Altered signal transduction from T-cell antigen receptor through the aberrant ZAP-70 changes the thresholds of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. Thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might also be crucial to the development of disease in a subset of patients with RA.     

Prediction of auditory spatial acuity from neural images on the owl's auditory space map

The owl can discriminate changes in the location of sound sources as small as 3 degrees and can aim its head to within 2 degrees of a source. A typical neuron in its midbrain space map has a spatial receptive field that spans 40 degrees--a width that is many times the behavioural threshold. Here we have quantitatively examined the relationship between neuronal activity and perceptual acuity in the auditory space map in the barn owl midbrain. By analysing changes in firing rate resulting from small changes of stimulus azimuth, we show that most neurons can reliably signal changes in source location that are smaller than the behavioural threshold. Each source is represented in the space map by a focus of activity in a population of neurons. Displacement of the source causes the pattern of activity in this population to change. We show that this change predicts the owl's ability to detect a change in source location.     

Precise Synthesis of Organometallic Dendrimers

1 Introduction Dendrimers possessing a regularly branched architecture and large spherical dimensions have attracted significant attention because of their unique and tunable properties as well as their potential applications. The incorporation of organometallic species into dendritic molecules has been attracting much attention, because the addition of properties characteristic of organometallic complexes, such as magnetic, electronic, and photo-optical properties, as well as reactivity may l…     

日本那须地区人工草地牧草生物量随时间变化的解析——Ⅰ地上生物量(英文)

为了揭示草地生态系统的现存生物量随时间的变化规律与气候条件和人为干扰(放牧压,施肥量等)之间的关系,从1974年开始至1994年,每年的4月至11月,在位于日本中部那须地区的国立草地研究所内的人造围栏放牧草场进行了放牧试验.结果表明,在1974至1994年的21年间,在不同放牧处理(放牧压分别为轻度和重度/施肥分少量和大量)的条件下,地上现存生物量的季节变化非常明显,其变化范围为:150～380gDWm-2.用4次方多项式检验表明牧草成长模式呈双峰曲线,每一年中不同放牧条件下地上现存生物量的最大值都出现在6月份左右,第二个峰值出现在9,10月份.复合回归分析的结果得出了体现现存生物量和气温,放牧压(或施肥量)之间的定量关系的多项回归方程式.协方差分析结果表明放牧压力,施肥量以及季节和年度的变化,以及他们之间的相互作用对现存生物量有着显著影响(P<0.05)或极显著影响(P<0.01).本研究表明在现存放牧强度下不会对地上生物量造成毁灭性的影响,而是在其承受范围之内.     

A genome-wide association study identifies three new risk loci for Kawasaki disease

We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A-BLK region at 8p22-23 (rs2254546, P = 8.2 × 10(-21)), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 × 10(-11)) and in the CD40 region at 20q13 (rs4813003, P = 4.8 × 10(-8)). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 × 10(-6)) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease.     

Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ～110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.     

Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns. Statistical and functional analyses yielded a list of recurrently mutated genes. Multiple chromatin regulators, including ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in ～50% of the tumors. Hepatitis B virus genome integration in the TERT locus was frequently observed in a high clonal proportion. Our whole-genome sequencing analysis of HCCs identified the influence of etiological background on somatic mutation patterns and subsequent carcinogenesis, as well as recurrent mutations in chromatin regulators in HCCs.