Regulation of doublesex pre-mRNA processing occurs by 3'-splice site activation

Sex-specific alternative processing of the doublesex (dsx) pre-mRNA controls somatic sexual differentiation in Drosophila melanogaster. Processing in the female-specific pattern results from the utilization of an upstream 3'-terminal exon and requires the activities of both the transformer (tra) and transformer-2 (tra-2) genes. Use of the more downstream male-specific terminal exons does not require the activities of these genes and is thus considered the default dsx-processing pattern. Here, we used transient expression of dsx pre-mRNAs in the presence or absence of tra and tra-2 gene products in Drosophila tissue culture cells to investigate the molecular mechanism controlling this alternative RNA-processing decision. These studies reveal that female-specific processing of dsx pre-mRNA is controlled by tra and tra-2 through the positive regulation of female-specific alternative 3'-terminal exon use. Delineation of cis-acting sequences necessary for regulation shows that a 540-nucleotide region from within the female exon is both necessary and sufficient for regulation. In addition, utilization of the female-specific 3'-splice site (3'SS) is regulated independently of female-specific polyadenylation. Regulated polyadenylation was obtained only in the presence of splicing, suggesting that activation of female-specific exon use occurs by 3'SS activation.     

噻芬太尼的主要药效和致依赖性潜力的实验研究

本文研究噻芬太尼的镇痛药效和制动作用,评价其致身体依赖性潜力。小鼠热板法测得噻芬太尼的镇痛作用强度分别为吗啡、芬太尼和埃托啡的3260,22和1.5倍。以瘫痪作为制动指标测得噻芬太尼对大鼠、家兔、狗和猴制动作用强度为埃托啡的2～3倍。小鼠跳跃实验和大鼠饮药液自然戒断实验表明该药具有一定致身体依赖性潜力。大鼠ⅳ快速成瘾实验及长达20周的猴身体依赖性实验则未出现依赖性戒断症状。     

Evidence for activation of both adrenergic and cholinergic nervous pathways by yohimbine,an alpha2-adrenoceptor antagonist*

Summary— Adrenoceptors are involved in the control of the activity of the autonomic nervous system and especially the sympathetic nervous system. Activation of alpha₂-adrenoceptors decreases sympathetic tone whereas their blockade has an opposite effect. However, previous investigations have shown that yohimbine (a potent alpha₂-adrenoceptor antagonist) increases salivary secretion through activation of cholinergic pathways. The aim of the present experiment was to investigate the involvement of both the sympathetic and the parasympathetic system in several pharmacological effects of yohimbine. For this purpose, salivary secretion and various endocrino-metabolic parameters (noradrenaline and insulin secretions, lipomobilization) were evaluated in conscious fasting dogs before and after blockade of either the sympathetic (with the β-adrenoceptor antagonist agent nadolol) or the parasympathetic (with the anticholinergic agent atropine) systems. Yohimbine alone (0.4 mgm?kg^?1, iv) increased within 5–15 minutes, plasma noradrenaline (600%), insulin levels (300%), free-fatty acids (79%) and salivary secretion (143%). Atropine (0.2 mgm?kg^?1, iv) suppressed yohimbine-induced salivary secretion (90%) but did not significantly modify the yohimbine induced changes in noradrenaline (312%), insulin (277%) and free-fatty acids (102%) plasma levels. Administration of nadolol (1 mgm?kg^?1, iv) did not change the magnitude of the increase in both noradrenaline plasma levels (550%) and salivary secretion (300%) induced by yohimbine. However, nadolol totally blunted the increase in insulin (15%) and free-fatty acids (4%) plasma levels. These results show that yohimbine-induced increase in salivary secretion is a cholinergic effect whereas the increase in insulin and free fatty acids can be explained by an increase in sympathetic tone. Thus, blockade of alpha₂-adrenoceptors induced a simultaneous activation of adrenergic and cholinergic systems. This pattern can explain the spectrum of side effects observed with yohimbine in man and suggests new potential clinical uses for alpha₂-adrenoceptor antagonists.     

Unresectable non-oat cell carcinoma of the lung: definitive radiation therapy

Between 1976 and 1983, 267 patients with non-oat cell carcinoma of the lung were treated with radiation therapy alone. One hundred thirty-four patients had squamous cell carcinoma; 69, large cell carcinoma; and 64, adenocarcinoma. Stage III carcinoma was diagnosed in 87% of the patients. Total radiation dose was less than 45 Gy in 69 patients (low dose group), 45-55 Gy in 161 (middle dose group), and 55-65 Gy in 37 (high dose group); dosage was 180-200 cGy daily, 5 days per week. Minimum follow-up was 3 years (median, 6 years). Tumor control within the radiation fields was achieved in 12%, 43%, and 78% of the low, middle, and high dose groups, respectively. A complete response rate of 13%, 23%, and 35% and an overall response of 43%, 71%, and 86% were seen in the low, middle, and high dose groups, respectively. The 5-year recurrence-free survival rate for all patients was 7% and was dependent on radiation dose and tumor response. This study indicates that tumor control and complete response rates are improved with a radiation dose of 55-65 Gy and that complete responders have improved survival.     

二甲胺四环素增强博安霉素的抗肿瘤转移作用

博安霉素对小鼠Lewis肺癌的肺转移有显著抑制作用;用等毒性剂量进行比较,博安霉素的肺转移抑制率高于丝裂霉素。单独给博安霉素(5mg·kg^-1)对肺转移抑制率为67%,对其中大转移瘤结(直径>2mm)的抑制率为85%;博安霉素与二甲胺四环素(5mg·kg^-1)联合使用时,对肺转移瘤以及时大转移瘤结的抑制率分别为88%和100%,两药相互作用指数CDI<0.5(P<0.01),表明二甲胺四环素能明显增强博安霉素的抗转移作用。酶联免疫测定证明,二甲胺四环素能降低肺巨细胞癌PG细胞IV型胶原酶的表达,Fura-2/AM荧光法测定,二甲胺四环素能显著降低PG细胞内游离Ca²⁺的水平。本研究结果提示博安霉素与二甲胺四环索联合用药可能有利于控制肿瘤转移,二甲胺四环素的增效机制可能与抑制IV型胶原酶的表达、干扰肿瘤侵袭与转移的过程有关。