Rational design of Rhizopus oryzae lipase with modified stereoselectivity toward triradylglycerols

The binding site of sn-1(3)-regioselective Rhizopus oryzae lipase (ROL) has been engineered to change the stereoselectivity of hydrolysis of triacylglycerol substrates and analogs. Two types of prochiral triradylglycerols were considered: 'flexible' substrates with ether, benzylether or ester groups, and 'rigid' substrates with amide or phenyl groups, respectively, in the sn-2 position. The molecular basis of sn-1(3) stereoselectivity of ROL was investigated by modeling the interactions between substrates and ROL, and the model was confirmed by experimental determination of the stereoselectivity of wild-type and mutated ROL. For the substrates, the following rules were derived: (i) stereopreference of ROL toward triradylglycerols depends on the substrate structure. Substrates with 'flexible' sn-2 substituents are preferably hydrolyzed at sn-1, 'rigid' substrates at sn-3. (ii) Stereopreference of ROL toward triradylglycerols can be predicted by analyzing the geometry of the substrate docked to ROL: if the torsion angle phiO3-C3 of glycerol is more than 150 degrees, the substrate will preferably be hydrolyzed in sn-1, otherwise in sn-3. For ROL, the following rules were derived: (i) residue 258 affects stereoselectivity by steric interactions with the sn-2 substituent rather than polar interactions. To a lower extent, stereoselectivity is influenced by mutations further apart (L254) from residue 258. (ii) With 'rigid' substrates, increasing the size of the binding site (mutations L258A and L258S) shifts stereoselectivity of hydrolysis toward sn-1, decreasing its size (L258F and L258F/L254F) toward sn-3.      

The function of a TiO2 compact layer in dye-sensitized solar cells incorporating "planar" organic dyes

We present a device based study into the operation of liquid electrolyte dye-sensitized solar cells (DSSC's) using organic dyes. We find that, for these systems, it is entirely necessary to employ a compact TiO2 layer between the transparent fluorine doped SnO2 (FTO) anode and the electrolyte in order to reduce charge recombination losses. By incorporation of a compact layer, the device efficiency can be increased by over 160% under simulated full sun illumination and more than doubled at lower light intensities. This is strong evidence that the more widely employed ruthenium based sensitizers act as to "insulate" the anode against recombination losses and that many planar organic dyes employed in DSSC's could greatly benefit from the use of a compact TiO2 blocking layer. This is in strong contrast to DSSC's sensitized with ruthenium based systems, where the introduction of compact TiO2 has only marginal effects on conversion efficiencies.     

Lapse-induced surges in craving influence relapse in adult smokers: An experimental investigation.

Objectives: Nearly all smokers who lapse experience a full-blown relapse, but the mediating mechanisms that contribute to this relationship are not well understood. A better understanding of these mechanisms would help to advance more effective relapse prevention treatments for smokers. The purpose of this study is to experimentally evaluate the effects of a programmed smoking lapse on smoking relapse and the effects of postlapse changes in craving on relapse. Method: Adult smokers (n = 63) who quit smoking with a brief cognitive–behavioral intervention and self-help materials were randomly assigned to one of two experimental conditions after 48 h of abstinence: No lapse (a no-smoking control/30-min waiting period) or lapse (smoking two cigarettes of their favored brand during a 30-min period). All participants were then followed daily for 14 days. Craving and biochemically verified self-reported abstinence were assessed on each follow-up day. Time (days) to relapse (7 consecutive days of smoking) was the main dependent measure. Results: Results of Cox regression analysis revealed that participants in the lapse condition relapsed more quickly than participants in the no-lapse condition (hazard ratio [HR] = 2.12, 95% confidence interval [CI] = [1.03, 4.35]). These effects were attributable, in part, to episodic increases in craving among participants in the lapse condition only (HR = 12.42, 95% CI =[2.00, 77.1]). Conclusions: Previously abstinent smokers who lapse are at risk for increased cigarette cravings and consequently, full-blown relapse. These results have implications for both cognitive–behavioral treatments for relapse prevention and for medications designed to help smokers manage cravings. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Win-shift and win-stay learning in the rainbow lorikeet (Trichoglossus haematodus).

The tendency to win-shift (to better learn to avoid, rather than return to, recently rewarded locations) has been demonstrated in a variety of nectarivorous birds and in honeybees. It is hypothesized to be a cognitive adaptation to the depleting nature of nectar. In the present study we report the first attempt to test for a win-shift bias in a nectarivorous parrot, the rainbow lorikeet (Trichoglossus hematodus). This species differs from others tested for a win-shift bias in that it is a facultative, rather than an obligate, nectarivore. We tested a captive-reared population of the birds on a shift/stay task at long and short retention intervals. The data show no evidence of either a win-shift or a win-stay bias. The birds demonstrated efficient spatial search ability and above chance performance for both shift and stay contingencies at long and short delays. These data suggest that an innate tendency to win-shift may not be present in all avian nectarivores, or that the role experience plays in shaping such behaviors is different for different species. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Do induced moods really influence health perceptions?

Objective. To determine whether induced mood alters health reports. Design. Randomized experiments testing a) mood influence on two global self-rated health (SRH) assessments (Study 1; N = 168) and b) testing whether illness relevant thinking moderates the influence of induced negative mood on SRH and physical symptom reports (Study 2; N = 143). Main Outcome Measures. Two global SRH items. Results. Effect sizes for induced mood were near zero across both studies (r's = 0.00-0.07). Aggregate analyses of induced mood studies showed a small adverse effect of induced negative mood on SRH, but these analyses masked roughly equal instances of better SRH among groups with worse mood. Conclusion. Published experimental research shows no consistent pattern of poorer SRH following negative mood induction in college-aged samples. Sample size and gender may account for variation in health ratings among induced mood groups. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Long-term function (6 years) of islet allografts in type 1 diabetes

Eight type 1 diabetic patients, ages 29-41 years, with mean diabetes duration of 23 years (range 18-29 years) received islet transplants from 1 to 5 donors. Seven patients had stable kidney allografts 1-11 years before the islet transplant, and one patient had a simultaneous islet-kidney allograft. Patients' blood glucose control was poor as reflected by the mean +/- SD HbA1c of 9.1 +/- 1.7% before transplant. Of the first three patients, two (1 and 3) achieved insulin independence for 36 and 38 days, respectively. Two recipients rejected their islet grafts within 1 month (2 and 8) and therefore were excluded from analysis. The HbA1c and insulin requirement of the six remaining patients who had persistent islet function for more than 60 days was significantly reduced from 9.3 +/- 1.9 to 6.4 +/- 1.0% (P = 0.002) and from 0.75 +/- 0.15 to 0.35 +/- 0.12 U x kg(-1) x day(-1) (P < 0.001), respectively. The two patients with the longest graft survival (4 and 6) achieved a normalization or near-normalization of their HbA1c levels during 6 years in the absence of severe episodes of hypoglycemia. As demonstrated by a decline in C-peptide response during Sustacal challenge tests over a 6-year period, there was a diminution of islet allograft function over time, despite persistence of normal or near normal HbA1c. We concluded that transplantation of allogeneic islets with an islet mass comparable with whole or segmental pancreas transplants in type 1 diabetic patients can result in long-term islet allograft function; further, we concluded that, in conjunction with small dosages of exogenous insulin, a functioning islet allograft can result in near-normalization of blood glucose levels and significant improvement in HbA1c. The occurrence of severe hypoglycemic episodes observed for patients in the Diabetes Control and Complications Trial was not observed in recipients with functioning islet transplants, despite the continuous need for exogenous insulin therapy to sustain normal HbA1c over the 6-year follow-up. The significant improvement in metabolic control observed for the patients described in this study, and the potential to significantly decrease or halt the progression of diabetic complications, support the continued application of islet allotransplantation as a treatment modality for type 1 diabetic patients.     

A low incidence of histiocytic sarcomatosis associated with infection of chickens with the HPRS-103 strain of subgroup J avian leukosis virus

Ten cases of histiocytic proliferative lesions in meat-type chickens associated in low incidence with infection by subgroup J avian leukosis virus (ALV) are described. Six were field cases in adult chickens from naturally infected flocks and four were from younger birds from transmission experiments with HPRS-103 ALV or the related acutely transforming ALV strains 17 and 879. The lesions were observed mostly in the spleen and in some cases in other organs. Microscopically, the lesions were comprised mainly of pleomorphic histiocyte-like cells admixed with variable numbers of lymphoid cells. More detailed studies were carried out on two birds at 4 and 7 wk of age following infection with HPRS-103 at 1 day of age. These birds had multiple small nodular lesions in the spleen, liver, and kidney that appeared similar cytologically to the more extensive lesions in older birds. Monoclonal antibodies specific for various lymphoid and nonlymphoid accessory cells were used in immunohistochemical studies to identify a predominance of cells of monocyte/macrophage lineage, and CD4- and CD8-positive lymphocytes, in the splenic nodules. Ultrastructural studies also revealed a similar mixed population of cells. Expression of ALV group-specific antigen, and gag and ALV-J env RNA, was not a marked feature of the histiocytic lesions. The proliferative histiocytic lesion is designated a histiocytic sarcomatosis.     

Tuberculosis and iron overload in Africa: a review

Both pulmonary tuberculosis and dietary iron overload are common conditions in sub-Saharan Africa. The incidence of tuberculosis has increased markedly over the last decade, primarily as a result of the rapid spread of infection with the human immunodeficiency virus (HIV). Dietary iron overload affects up to 10% of adults in rural populations and is characterized by heavy iron deposition both in parenchymal cells and in macrophages. Mycobacterium tuberculosis grows within macrophages and, at the same time, the antimicrobial function of macrophages is important in the body's defence against tuberculosis. In vitro, the loading of macrophages with iron reduces the response of these cells to activation by interferon-gamma and diminishes their toxicity against micro-organisms. In the clinical setting, dietary iron overload appears to increase the risk for death from tuberculosis even in the absence of the acquired immunodeficiency syndrome. The combination of dietary iron overload and infection with the HIV, with impaired function of both macrophages and T-cells, may make patients especially vulnerable to tuberculosis. It is possible that the prevention and treatment of dietary iron overload could contribute to the control of tuberculosis in African populations.     

Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor

L-745,870,(3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H- pyrollo[2,3-b] pyridine, was identified as a selective dopamine D4 receptor antagonist with excellent oral bioavailability and brain penetration. L-745,870 displaced specific binding of 0.2 nM [3H] spiperone to cloned human dopamine D4 receptors with a binding affinity (Ki) of 0. 43 nM which was 5- and 20-fold higher than that of the standard antipsychotics haloperidol and clozapine, respectively. L-745,870 exhibited high selectivity for the dopamine D4 receptor (>2000 fold) compared to other dopamine receptor subtypes and had moderate affinity for 5HT2, sigma and alpha adrenergic receptors(IC50 < 300 nM). In vitro, L-745,870 (0.1-1 microM) exhibited D4 receptor antagonist activity, reversing dopamine (1 microM) mediated 1) inhibition of adenylate cyclase in hD4HEK and hD4CHO cells; 2) stimulation of [35S] GTPgammaS binding and 3) stimulation of extracellular acidification rate, but did not exhibit any significant intrinsic activity in these assays. Although standard antipsychotics increase dopamine metabolism or plasma prolactin levels in rodents, L-745,870 (相似文献   

Crystal structure of DNA photolyase from Anacystis nidulans

Micronutrient deficiencies probably have few direct effects on the functioning of immune cells. The main effect appears to be a reduction in cell mass that may indirectly affect immune cell function, particularly where T helper cell numbers are reduced. Results of many human studies are contradictory. Some of this contradiction may be accounted for by the fact that disease may lower concentrations of micronutrients in plasma that may be misinterpreted as deficiency. Low plasma vitamin A concentrations however appear to impair immune responsiveness and have deleterious effects on membrane integrity and mucosal function. Zinc may have similar effects on gut integrity and appears to be particularly useful in the treatment of acute diarrhoea. Low concentrations of other nutrients such as ascorbate and iron, may not necessarily impair immune function. Low plasma ascorbate may assist the removal of iron from plasma and low iron concentrations appear to increase the cytotoxicity of macrophages.