Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination

Inhibitor of apoptosis (IAP) proteins are negative regulators of cell death. IAP family members contain RING domains that impart E3 ubiquitin ligase activity. Binding of endogenous or small-molecule antagonists to select baculovirus IAP repeat (BIR) domains within cellular IAP (cIAP) proteins promotes autoubiquitination and proteasomal degradation and so releases inhibition of apoptosis mediated by cIAP. Although the molecular details of antagonist-BIR domain interactions are well understood, it is not clear how this binding event influences the activity of the RING domain. Here biochemical and structural studies reveal that the unliganded, multidomain cIAP1 sequesters the RING domain within a compact, monomeric structure that prevents RING dimerization. Antagonist binding induces conformational rearrangements that enable RING dimerization and formation of the active E3 ligase.     

The fungicide captan reduces nuclear DNA content in maize seedlings

Captan, a major fungicide used by the US maize industry, was studied to determine its effect on the nuclear DNA content of maize (Zea mays L.) seedlings. Captan was applied to kernels at the recommended agronomic rates. The nuclear DNA content of the seedlings was determined by flow cytometry. In two maize hybrids examined, a reduction in nuclear DNA content was observed. Two different fluorochromes, with different staining mechanisms, were used to determine nuclear DNA content. Both of these fluorochromes revealed a reduction in nuclear DNA. Captan is reported to inhibit DNA synthesis in several animal systems. The reduction of maize nuclear DNA observed in this study may be a result of DNA synthesis inhibition induced by captan.     

Effects of a peripheral alpha2 adrenergic-receptor antagonist on the hemodynamic changes induced by medetomidine administration in conscious dogs

OBJECTIVE: To evaluate the effects of administration of a peripheral alpha(2)-adrenergic receptor antagonist (L-659,066), with and without concurrent administration of glycopyrrolate, on cardiopulmonary effects of medetomidine administration in dogs. ANIMALS: 6 healthy adult dogs. PROCEDURES: Dogs received saline (0.9% NaCl) solution (saline group), L-659,066 (group L), or L-659,066 with glycopyrrolate (group LG). These pretreatments were followed 10 minutes later by administration of medetomidine in a randomized crossover study. Hemodynamic measurements and arterial and mixed-venous blood samples for blood gas analysis were obtained prior to pretreatment, 5 minutes after pretreatment, and after medetomidine administration at intervals up to 60 minutes. RESULTS: After pretreatment in the L and LG groups, heart rate, cardiac index, and partial pressure of oxygen in mixed-venous blood (PvO2) values were higher than those in the saline group. After medetomidine administration, heart rate, cardiac index, and PvO2 were higher and systemic vascular resistance, mean arterial blood pressure, and central venous pressure were lower in the L and LG groups than in the saline group. When the L and LG groups were compared, heart rate was greater at 5 minutes after medetomidine administration, mean arterial blood pressure was greater at 5 and 15 minutes after medetomidine administration, and central venous pressure was lower during the 60-minute period after medetomidine administration in the LG group. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of L-659,066 prior to administration of medetomidine reduced medetomidine-induced cardiovascular changes in healthy dogs. No advantage was detected with concurrent administration of L-659,066 and glycopyrrolate.     

Cardiopulmonary effects of anesthetic induction with thiopental, propofol, or a combination of ketamine hydrochloride and diazepam in dogs sedated with a combination of medetomidine and hydromorphone

OBJECTIVE: To evaluate the cardiopulmonary effects of anesthetic induction with thiopental, propofol, or ketamine hydrochloride and diazepam in dogs sedated with medetomidine and hydromorphone. ANIMALS: 6 healthy adult dogs. PROCEDURES: Dogs received 3 induction regimens in a randomized crossover study. Twenty minutes after sedation with medetomidine (10 microg/kg, IV) and hydromorphone (0.05 mg/kg, IV), anesthesia was induced with ketamine-diazepam, propofol, or thiopental and then maintained with isoflurane in oxygen. Measurements were obtained prior to sedation (baseline), 10 minutes after administration of preanesthetic medications, after induction before receiving oxygen, and after the start of isoflurane-oxygen administration. RESULTS: Doses required for induction were 1.25 mg of ketamine/kg with 0.0625 mg of diazepam/kg, 1 mg of propofol/kg, and 2.5 mg of thiopental/kg. After administration of preanesthetic medications, heart rate (HR), cardiac index, and PaO(2) values were significantly lower and mean arterial blood pressure, central venous pressure, and PaCO(2) values were significantly higher than baseline values for all regimens. After induction of anesthesia, compared with postsedation values, HR was greater for ketamine-diazepam and thiopental regimens, whereas PaCO(2) tension was greater and stroke index values were lower for all regimens. After induction, PaO(2) values were significantly lower and HR and cardiac index values significantly higher for the ketamine-diazepam regimen, compared with values for the propofol and thiopental regimens. CONCLUSIONS AND CLINICAL RELEVANCE: Medetomidine and hydromorphone caused dramatic hemodynamic alterations, and at the doses used, the 3 induction regimens did not induce important additional cardiovascular alterations. However, administration of supplemental oxygen is recommended.     

CD4+CD25+ regulatory T cells are infected and activated during acute FIV infection

HIV-induced AIDS may be mediated by the activation of immunosuppressive CD4+CD25+ T regulatory cells (Treg cells). Treg cells have been shown to regulate CD4+ and CD8+ immune responses to HIV and FIV antigens in vitro. We tested the hypothesis that Treg cells become infected and activated during the acute infection with FIV leading to the suppression of CD4+ T helper cell responses. Cats were experimentally infected with FIV-NCSU1 and blood and lymph node cells were collected at weekly intervals following inoculation. Real-time RT-PCR was used to determine plasma viremia and the relative expression of FIV, FoxP3, TGF-beta, and GAPDH mRNA copies in CD4+CD25+ and CD4+CD25- T cell subsets. Flow cytometry was used to assess the absolute numbers of each cell type and the expression of surface TGF-beta and intracellular FoxP3 in CD4+CD25+ and CD4+CD25- T cells at each time-point. Treg suppression of IL-2 production in CD4+ T helper cells was assessed by ELISPOT assays. Our results showed that peak viremia occurred at 2 weeks post infection and correlated with maximal infectivity in CD4+CD25+ T cell populations. FIV-gag-mRNA levels were higher in CD4+CD25+ T cells than CD4+CD25- T cells throughout the acute phase of infection. Induction of FoxP3 and TGF-beta indicated activation of Treg cells during the acute stage infection, which was confirmed by Treg cell suppression of IL-2 production by CD4+ Th cells in an ELISPOT assay. Our findings support the hypothesis that early activation of Treg immunosuppressor function may limit an effective anti-FIV response, contributing to the establishment of chronic infection and the immunodeficiency caused by this virus.     

美国纽约州的奶牛业发展水平及其原因分析

自20世纪60年代以来,纽约州奶牛场及奶牛存栏数持续减少,但奶牛场养殖规模不断扩大,奶牛产奶率、劳动生产率、资金周转率和利润率不断提高,奶牛场净收入增加。本文利用详细具体的统计和调查数据总结分析了美国纽约州奶牛业发展的历史变化与现状。纽约州在奶牛育种、饲养、经营管理、社会化服务和奶牛合作社等方面的成功做法与经验值得借鉴。     

Hyalinizing pancreatic adenocarcinoma in six dogs

Exocrine pancreatic carcinoma is a particularly malignant neoplasm of the dog. Clinical and pathologic findings of an unusual variant of exocrine pancreatic neoplasia termed hyalinizing pancreatic adenocarcinoma were evaluated in 6 dogs. On microscopic examination, neoplasms were composed of tubules and acini of epithelial cells, with bright eosinophilic granular apical cytoplasm. Tubular lumina and tumor stroma contained abundant hyaline material that resembled amyloid. The hyaline material was not congophilic, and tumor cells and hyaline material were immunohistochemically negative for amyloid A, immunoglobulin light chains (kappa and lambda), amylin (islet amyloid polypeptide), laminin, and alpha(1)-antitrypsin. Two patients survived longer than 15 months after diagnosis; one of these dogs was untreated and had grossly evident metastasis at the time of diagnosis. The deaths of the other 4 dogs occurred as a result of poor recovery after partial pancreatectomy or in association with other concurrent life-threatening conditions. Two dogs were diagnosed with panniculitis, a condition rarely associated with pancreatic disease. Further evaluation is needed to determine the composition and biologic significance of intratumor hyaline material. Studies that associate exocrine pancreatic carcinoma grade and histologic subtype with prognostic outcomes in the dog are warranted such that appropriate therapy can be elected.