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The unoccupied electronic structure for the Sr_14Cu_24O_41 family of two-leg ladder compounds was investigated for different partial substitutions of Sr^2+ by Ca^2+, leaving the nominal hole count constant, and by Y^3+ or La^3+, reducing the nominal hole count from its full value of 6 per formula unit. Using polarization-dependent x-ray absorption spectroscopy on single crystals, hole states on both the chain and ladder sites could be studied. While for intermediate hole counts all holes reside on O sites of the chains, a partial hole occupation on the ladder sites in orbitals oriented along the legs is observed for the fully doped compound Sr_14Cu_24O_41. On substitution of Ca for Sr orbitals within the ladder planes but perpendicular to the legs receive some hole occupation as well., Comment: 10 pages RevTeX style with 7 embedded figures + 1 table; accepted by Phys. Rev. B

著者らは, ニワトリの脳幹内に局所的に注入した 5-hydroxytryptamine (5-HT; serotonin) が, 脳波および心電図にどのような作用を及ぼすかを検討し, 次の結果を得た. 1) 5-HT (10～30μl) を後部視床背, 腹側部領域および後部視床下部領域に注入すると, 2分前後に脳波の非同期化(20～30μV, 20～30Hz)が, まず注入側に現われ, 6～8分後に高振幅波(80～100μV, 1～3Hz)が, 上述の非同期の波に混入し, 次いで, 高振幅, 徐波(100～120μV, 2～3Hz)が現われ, 60分前後継統して, 注入前の脳波にもどった. 一方, 反対側の脳波では, このような変化は見られなかった. 2) 5-HTを後部視床背, 腹側部領域に注入すると, 心搏動数の著しい減少が, 30秒以内に起こった. この減少は8分以上継続して, その後次第に増加し, 26分後には, 注入前の心搏動数にもどった. 3) 5-HTが脳波に及ぼす影響は, 脳への血液供給の不足を起こす間接的な作用の結果とは考えられない. 4) 後部視床背・腹側部領域および後部視床下部領域に注入された5-HTは, 約1mm3の球状に拡散することから考えると, 上記の脳波の二相性の変化に関与する受容器は, これらの領域に存在するものと思われる.

70～90日令の白色レグホン種の雄に, 寒冷を付与するとともに, クロールプロマジン(CPZと略す)を20mg/kg静脉内に注射し, 血糖, 血中乳酸, 肝グリコーゲンおよび筋グリコーゲンを測定した. その結果は, 次のとおりである. 1) 18時間飢餓鶏を保定し, 寒冷を付与するとともにCPZを投与すると, 60分以内に一過性過血糖が起こるが, その後, 血糖は減少した. 加温によって体温の正常値への回復を図ると, 血糖もまた上昇回復する傾向を示した. この際, 戦慄は全く起こらなかった. 2) 正常鶏に寒冷を付与するとともにCPZを投与すると, 血糖は30分で増加し, 肝グリコーゲンは次第に減少した. 血中乳酸は30分で増加し, 筋グリコーゲンは30分で減少した. 本研究を遂行するにあたり, 終始, 鞭達および助言を賜わった東京大学教授大久保義夫先生に深く感謝申し上げる.

FALCK(1962)およびCARLSO等(1962)によって確立された螢光組織化学法を用いて,ニワトリの消化管(食道・嗜のう・腺胃・筋胃・十二指腸・回腸・直腸・盲腸)におけるmonoamincsの分布を追究し,次の結果を得た.catccholamine含有線維(緑色螢光線維)は,観察したすべての消化管の各部で,小動脈壁・筋層および壁内神経叢に見られた.もっとも顕著な特徴は,消化管のすべての部位で,縦走筋層内の壁内神経叢に強または弱発色のCA線維が存在することであった.更に,十二指腸・回腸・直腸および盲腸の粘膜下組織の壁内神経叢においても,強い緑色螢光が見られた,これらの事実は,従来choline作動性と考えられていた壁内神経叢が,adrcna11ne作動性調節を受けることを示唆する,5-hydroxytryptaminc含有細胞(黄色螢光細胞)は,腺胃・十二指腸・回腸・直腸および盲腸の粘膜層のLieberkuehn腺に分布し,enterochrom親和細胞と一致した.粘膜面1mm2当りの5一HT細胞の数は,直腸が最も多かった.一方,食道・嗜のうおよび筋胃では,5-H丁細胞は認められなかった.rescrpine(3mg/kg)処理後4時間と18時間の標本では,catccholamincの緑色螢光は,全て完全に消失したが,5-hydroxytryptamineの黄色螢光は,一部消失せず残存した.

Germline TSC1 or TSC2 mutations cause Tuberous Sclerosis Complex (TSC), a hamartoma syndrome with lung involvement. To explore the potential interaction between TSC1 and KRAS activation in lung cancer, mice were generated in which Tsc1 loss and KrasG12D expression occur in a small fraction of lung epithelial cells. Mice with combined Tsc1-KrasG12D mutation had dramatically reduced tumor latency (median survival 11.6 – 15.6 weeks) in comparison to KrasG12D alone mutant mice (median survival 27.5 weeks). Tsc1-Kras G12D tumors showed consistent activation of mTORC1, and responded to treatment with rapamycin leading to significantly improved survival, while rapamycin had minor effects on cancers in KrasG12D alone mice. Loss of heterozygosity for TSC1 or TSC2 was found in 22% of 86 human lung cancer specimens. However, none of 80 lung cancer lines studied showed evidence of lack of expression of either TSC1 or TSC2 or a signaling pattern corresponding to complete loss. These data indicate Tsc1 loss synergizes with Kras mutation to enhance lung tumorigenesis in the mouse, but that this is a rare event in human lung cancer. Rapamycin may have unique benefit for lung cancer patients in which TSC1/TSC2 function is limited.

Glycerol kinase deficiency (GKD) is an X-linked recessive trait that occurs in association with congenital adrenal hypoplasia (AH) and developmental delay with or without congenital dystrophic myopathy. Several such patients have recently been reported to have cytological deletions of chromosome region Xp21 and/or of DNA markers that map near the locus for Duchenne muscular dystrophy (DMD) in band Xp21. We have examined the initial family reported in the literature and, using prometaphase chromosome studies and Southern blot analysis with 13 different DNA probes derived from band Xp21, have found no deletions within this region of the X chromosome. When DNA samples from six other unrelated affected males were analyzed, four of them were found to have different-size deletions within Xp21. Thus, the form of GKD associated with AH and dystrophic myopathy exhibits significant genetic heterogeneity at the DNA level. No deletions were detected in two patients with isolated GK deficiency. Comparison of our molecular studies of unrelated patients with deletions of DNA segments allows us to define the region of Xp21 (between probes J-Bir and L1.4) that most likely contains the genes for GKD and AH. This location is distal to the DMD locus. The patients with progressive muscular dystrophy tended to have larger deletions that include markers known to derive from the DMD locus, while GKD/AH/dystrophic-myopathy patients without current evidence of deletion seemed to have a milder, nonprogressive form of congenital myopathy.

Item does not contain fulltext Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.

Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components.In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography.We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population.Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.).