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811.
Ahad AM Zuohe S Du-Cuny L Moses SA Zhou LL Zhang S Powis G Meuillet EJ Mash EA 《Bioorganic & medicinal chemistry》2011,19(6):2046-2054
Disruption of the phosphatidylinositol 3-kinase/AKT signaling pathway can lead to apoptosis in cancer cells. Previously we identified a lead sulfonamide that selectively bound to the pleckstrin homology (PH) domain of AKT and induced apoptosis when present at low micromolar concentrations. To examine the effects of structural modification, a set of sulfonamides related to the lead compound was designed, synthesized, and tested for binding to the expressed PH domain of AKT using a surface plasmon resonance-based competitive binding assay. Cellular activity was determined by means of an assay for pAKT production and a cell killing assay using BxPC-3 cells. The most active compounds in the set are lipophilic and possess an aliphatic chain of the proper length. Results were interpreted with the aid of computational modeling. This paper represents the first structure-activity relationship (SAR) study of a large family of AKT PH domain inhibitors. Information obtained will be used in the design of the next generation of inhibitors of AKT PH domain function. 相似文献
812.
Zain Ul Abidin Habib Ul Hassan Zubia Masood Naseem Rafique Bilal Ahamad Paray Karim Gabol Muhammad Ishaq Ali Shah Aneela Gulnaz Asim Ullah Talha Zulfiqar Mohammad Abdul Momin Siddique 《Saudi Journal of Biological Sciences》2022,29(4):3075
Rainbow trout Oncorhynchus mykiss has a great nutritional value and delicious taste. A 90-days experimental trial was conducted to investigate the effect of dietary leaf extract of neem tree Azadirachta indica as a feeding supplement on the growth performance and proximate composition of O. mykiss. Four experimental diets were designed as T1 (with 5% A. indica leaf extract), T2 (with 7% of A. indica leaf extract), T3 (with 10% A. indica leaf extract), and T4 (control group feed with a regular diet with 0% A. indica leaf extract). The average initial weight of fry 0.4 ± 0.14 g was stocked at 25 fish/tank with two replicates per treatment (4 × 2 = 8). After 90 days of the experimental trial, One-way ANOVA showed significant differences in final body weight, weight gain, specific growth rate, feed conversion ratio, and survival rate among the treatment groups (p < 0.05). The highest final body weight (48.10 g) and weight gain (47.70 g) was observed in T2 with 7% A. indica leaf extract, which was significantly different from the other treatments (p < 0.05). The lowest FCR was recorded in T2 (1.90), which was significantly different compared to other treatment groups (p < 0.05). Inclusion of A. indica leaf extract in formulated feed for rainbow trout had significant effects in the hepatosomatic index, viscerosomatic index and Fulton’s condition factor (p < 0.05), but there was no significant difference in the survival rate of rainbow trout fry treated with different experimental diets (p > 0.05). The phenomenal regression indicates that 7.5% A. indica inclusion is optimum for best growth performance for rainbow trout under a controlled environment. Thus, the present study suggests that the dietary leaf extract has performed an excellent nutritional supplement by enhancing growth performance and health conditions of rainbow trout in the hatchery conditions. 相似文献
813.
两种种植体系下地下水硝态氮含量变化 总被引:4,自引:0,他引:4
寿光作为全国闻名的保护地蔬菜产区,过量施肥的现象非常普遍。为了解集约化大棚蔬菜种植区地下水中硝酸盐的含量变化状况,于2003~2005年对寿光市大田(小麦-玉米)、大棚(一年两茬番茄)两种不同的种植体系下农田灌溉水和农村饮用水水井进行了定点跟踪监测。结果表明:大田区地下水中硝态氮的含量随着时间的变化波动很小,农村饮用水中硝态氮含量没有超标现象;随着时间推移,大棚区灌溉水井中硝态氮含量年内(从年初到年末)呈明显的上升趋势,年际间则存在有规律的波动并逐年升高;灌溉水中硝态氮平均含量普遍高于饮用水,浅层地下水明显高于深层地下水;无论大棚区还是大田区,井深不同对地下水的硝态氮含量影响差异很大,浅井中硝态氮的含量明显高于深井。大棚区农村饮用水硝态氮含量超标现象非常普遍,对国家饮用水标准(20mg·L^-1)超标率最高达37.50%,平均为14.06%;对WHO推荐饮用水上限(10mg·L^-1)超标率最高达56.25%,平均为42.19%,硝态氮最高含量45.60mg·L^-1。集约化大棚蔬菜栽培模式已经对农村地下水造成了很大的硝态氮污染,饮用水中较高的硝酸盐含量已经对当地居民的健康构成了潜在的威胁。 相似文献
814.
Ahmad Khaldun Ismail Muhammad Nadzmi Hadi Abd Hamid Nur Alissa Ariff Vera Effa Rezar Frederic Ng Wan Chee Goh Nur Syafiqah Abdul Samat Annuar Muhammad Zuljamal Osman Ruth Sabrina Safferi Zainalabidin Mohamed@Ismail 《PLoS neglected tropical diseases》2023,17(1)
Pit vipers from the genus Tropidolaemus are identified as one of the common causes of snake bite from venomous species in Malaysia. All Tropidolaemus species bite cases referred to the Remote Envenomation Consultation Services (RECS) between 2015–2021 were included. A total of 4,718 snake-related injuries cases consulted to RECS with 310 (6.6%) involved Tropidolaemus species; of these 190 (61.3%) were T. subannulatus and 120 (38.7%) T. wagleri. All the T. subannulatus cases occurred in Sabah and Sarawak while all cases of T. wagleri occurred in Peninsular Malaysia. The majority of patients were male (74.8%) and adults between 18–59 years old (61.2%). The upper limb (56.6%) was the most frequent anatomical region involved. Most cases were non-occupationally related (75.4%). Bites from both species caused local pain (77.1%) and swelling (27.2%). Most patients complained of mild pain (48.0%). Paracetamol (40.0%) was the most common analgesic prescribed. Antivenom was not indicated in all cases. Two patients were given antivenom inappropriately before RECS consultation. Most patients (54.7%) needed hospital observation for less than 24 hours. No deaths occurred in the group studied. 相似文献
815.
Alistair J.P. Brown Rudi J. Planta Fajar Restuhadi David A. Bailey Philip R. Butler Jose L. Cadahia M.Esperanza Cerdan Martine De Jonge David C.J. Gardner Manda E. Gent Andrew Hayes Carin P.A.M. Kolen Luis J. Lombardia Abdul Munir Abdul Murad Rachel A. Oliver Mark Sefton Johan M. Thevelein Helene Tournu Yvon J. van Delft Dennis J. Verbart Joris Winderickx Stephen G. Oliver 《The EMBO journal》2001,20(12):3177-3186
816.
Chattopadhyay G Khan AQ Sen G Colino J DuBois W Rubtsov A Torres RM Potter M Snapper CM 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(11):7523-7534
IgG antipolysaccharide (PS) and antiprotein responses to Streptococcus pneumoniae (Pn) are both CD4(+) T cell dependent. However, the primary IgG anti-PS response terminates more quickly, uses a shorter period of T cell help, fails to generate memory, and is more dependent on membrane Ig (mIg) signaling. We thus determined whether this limited anti-PS response to Pn reflected a greater propensity of PS-specific B cells to undergo apoptosis. We used mice that constitutively expressed the antiapoptotic protein Bcl-x(L) or Bcl-2 as a B cell-specific transgene. Both transgenic (Tg) mice exhibited increased absolute numbers of splenic B-1 and peritoneal B-1b and B-2 cells, subsets implicated in anti-PS responses, but not in marginal zone B (MZB) cells. Both Tg mouse strains elicited, in an apparently Fas-independent manner, a more prolonged and higher peak primary IgM and IgG anti-PS, but not antiprotein, response to Pn, but without PS-specific memory. A similar effect was not observed using purified PS or pneumococcal conjugate vaccine. In vitro, both splenic MZB and follicular Tg B cells synthesized DNA at markedly higher levels than their wild-type counterparts, following mIg cross-linking. This was associated with increased clonal expansion and decreased apoptosis. Using Lsc(-/-) mice, the Pn-induced IgG response specific for the capsular PS was found to be almost entirely dependent on MZB cells. Collectively, these data suggest that apoptosis may limit mIg-dependent clonal expansion of PS-specific B cells during a primary immune response to an intact bacterium, as well as decrease the pool of PS-responding B cell subsets. 相似文献
817.
Human rhinovirus type 54 infection via heparan sulfate is less efficient and strictly dependent on low endosomal pH 下载免费PDF全文
K-type major-group human rhinoviruses (HRVs) (including HRV54) share a prominent lysine residue in the HI surface loop of VP1 with all minor-group HRVs. Despite the presence of this residue, they cannot use members of the low-density lipoprotein receptor family for productive infection. Reexamining all K-type viruses for receptor usage, we noticed that HRV54 is able to replicate in RD cells that lack the major-group receptor intercellular adhesion molecule 1 (ICAM-1). By using receptor blocking assays, inhibition of sulfation, enzymatic digestion, and proteoglycan-deficient cell lines, we show here that wild-type HRV54, without any adaptation, uses heparan sulfate (HS) proteoglycan as an alternate receptor. However, infection via HS is less efficient than infection via ICAM-1. Moreover, HRV54 has an acid lability profile similar to that of the minor-group virus HRV2. In ICAM-1-deficient cells its replication is completely blocked by the H(+)-ATPase inhibitor bafilomycin A1, whereas in ICAM-1-expressing cells it replicates in the presence of the drug. Thus, use of a "noncatalytic" receptor requires the virus to be highly unstable at low pH. 相似文献
818.
Role of EAL-containing proteins in multicellular behavior of Salmonella enterica serovar Typhimurium
GGDEF and EAL domain proteins are involved in turnover of the novel secondary messenger cyclic di(3'-->5')-guanylic acid (c-di-GMP) in many bacteria. The rdar morphotype, a multicellular behavior of Salmonella enterica serovar Typhimurium characterized by the expression of the extracellular matrix components cellulose and curli fimbriae is controlled by c-di-GMP. In this work the roles of the EAL and GGDEF-EAL domain proteins on rdar morphotype development were investigated. Knockout of four of 15 EAL and GGDEF-EAL domain proteins upregulated rdar morphotype expression and expression of CsgD, the central regulator of the rdar morphotype, and partially downregulated c-di-GMP concentrations. More-detailed analysis showed that the EAL domain protein STM4264 and the GGDEF-EAL domain protein STM1703, which highly downregulated the rdar morphotype, have overlapping yet distinct functions. Another subset of EAL and GGDEF-EAL domain proteins influenced multicellular behavior in liquid culture and flagellum-mediated motility. Consequently, this work has shown that several EAL and GGDEF-EAL domain proteins, which act as phosphodiesterases, play a determinative role in the expression level of multicellular behavior of Salmonella enterica serovar Typhimurium. 相似文献
819.
820.
McFalls EO Kelly RF Hu Q Mansoor A Lee J Kuskowski M Sikora J Ward HB Zhang J 《American journal of physiology. Heart and circulatory physiology》2007,293(5):H2945-H2951
Within hibernating myocardium, it is uncertain whether a normal energetic state is present at baseline and whether maintaining that energy state during a catecholamine challenge is dependent on ATP-dependent potassium channel opening. In this study, 16 swine underwent a thoracotomy with placement of an external constrictor on the left anterior descending coronary artery (LAD) (hibernation model). Seven additional swine underwent a sham operation. At 10 wk, the myocardial energetic state in the LAD region was assessed by (31)P-NMR spectroscopy, and the ratio of phosphocreatine to ATP (PCr/ATP) was determined at baseline, during glibenclamide treatment (0.5 mg/kg bolus with 50 microg/min iv), and during addition of dobutamine (40 microg x kg(-1) x min(-1) iv). At baseline, transmural blood flow in the LAD and remote region was 0.75 +/- 0.11 and 0.88 +/- 0.09 ml x min(-1) x g(-1), respectively (P < 0.01), in hibernating hearts and 0.83 +/- 0.12 and 0.88 +/- 0.15 ml x min(-1) x g(-1), respectively (not significant), in sham-operated hearts. Under basal conditions, PCr/ATP in the LAD region of hibernating and sham pigs was 2.15 +/- 0.04 and 2.11 +/- 0.05, respectively (not significant). In sham pigs, addition of dobutamine to glibenclamide increased the double product from 10.4 +/- 0.8 to 23.9 +/- 4.0 mmHg x beats x min(-1) x 1,000 (P < 0.05) and decreased transmural PCr/ATP from 2.06 +/- 0.06 to 1.69 +/- 0.06 (P < 0.05). Dobutamine increased the double product in hibernating pigs in a similar fashion and, despite a 40% lower blood flow response, induced an equivalent decrease in PCr/ATP from 2.04 +/- 0.04 to 1.73 +/- 0.08 (P < 0.05). In conclusion, we found that, in chronic hibernating swine myocardium with reduced basal blood flow and perfusion reserve, the transmural energetic state, defined by PCr/ATP, is normal during addition of dobutamine, despite inhibition of ATP-dependent potassium channel opening with glibenclamide. These data suggest that important adaptations other than the ATP-dependent potassium channel opening allow hibernating myocardium to operate over a lower range of the oxygen supply-demand relationship to protect against myocardial ischemia. 相似文献