Miracle-dz/UniFAR-FTUs huggingface dataset:
P2Y2 nucleotide receptor signaling in human monocytic cells: Activation, desensitization and coupling to mitogen‐activated protein kinases

Activation of P2Y2 receptors by extracellular nucleotides has been shown to induce phenotypic differentiation of human promonocytic U937 cells that is associated with the inflammatory response. The P2Y2 receptor agonist, UTP, induced the phosphorylation of the MAP kinases MEK1/2 and ERK1/2 in a sequential manner, since ERK1/2 phosphorylation was abolished by the MEK1/2 inhibitor PD 098059. Other results indicated that P2Y2 receptors can couple to MAP kinases via phosphatidylinositol 3‐kinase (PI3K) and c‐src. Accordingly, ERK1/2 phosphorylation induced by UTP was inhibited by the PI3K inhibitors, wortmannin and LY294002, and the c‐src inhibitors, radicicol and PP2, but not by inhibitors of protein kinase C (PKC). The phosphorylation of ERK1/2 was independent of the ability of P2Y2 receptors to increase the concentration of intracellular free calcium, since chelation of intracellular calcium by BAPTA did not diminish the phosphorylation of ERK1/2 induced by UTP. A 5‐minute treatment with UTP reduced U937 cell responsiveness to a subsequent UTP challenge. UTP‐induced desensitization was characterized by an increase in the EC50 for receptor activation (from 0.44 to 9.3 μM) and a dramatic (∼75%) decrease in the maximal calcium mobilization induced by a supramaximal dose of UTP. Phorbol ester treatment also caused P2Y2 receptor desensitization (EC50 = 12.3 μM UTP and maximal calcium mobilization reduced by ∼33%). The protein kinase C inhibitor GF 109203X failed to significantly inhibit the UTP‐induced desensitization of the P2Y2 receptor, whereas the protein phosphatase inhibitor okadaic acid blocked receptor resensitization. Recovery of receptor activity after UTP‐induced desensitization was evident in cells treated with agonist for 5 or 30 min. However, P2Y2 receptor activity remained partially desensitized 30 min after pretreatment of cells with UTP for 1 h or longer. This sustained desensitized state correlated with a decrease in P2Y2 receptor mRNA levels. Desensitization of ERK1/2 phosphorylation was induced by a 5‐minute pretreatment with UTP, and cell responsiveness did not return even after a 30‐minute incubation of cells in the absence of an agonist. Results suggest that desensitization of the P2Y2 receptor may involve covalent modifications (i.e., receptor phosphorylation) that functionally uncouple the receptor from the calcium signaling pathway, and that transcriptional regulation may play a role in long‐term desensitization. Our results indicate that calcium mobilization and ERK1/2 phosphorylation induced by P2Y2 receptor activation are independent events in U937 monocytes. © 2001 Wiley‐Liss, Inc.
Initial therapy with nucleoside reverse transcriptase inhibitor-containing regimens is more effective than with regimens that spare them with no difference in short-term fat distribution: Hippocampe-ANRS 121 Trial.

OBJECTIVES The aim of this study was to evaluate the impact on body fat of nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens compared with NRTI-containing therapy in HIV-1-infected antiretroviral (ARV)-naive patients. METHODS A randomized, multicentre, open-label trial in ARV-naive patients. Subjects were randomized (2:1:1) to receive: (i) an NRTI-sparing regimen consisting of a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus a boosted protease inhibitor (PI/r); or (ii) an NRTI-containing regimen of (a) a PI/r plus two NRTIs or (b) an NNRTI plus two NRTIs. The primary endpoint was the change in subcutaneous limb fat measured by dual-energy X-ray absorptiometry at week (W) 96. Secondary endpoints included the proportion of patients with treatment failure, plasma HIV-RNA (pVL) <50 copies/mL and safety. RESULTS One hundred and seventeen patients were enrolled between November 2003 and May 2004: 26% female; 42% from sub-Saharan Africa; median plasma HIV-RNA (pVL) 5.1 log(10) copies/mL; median CD4 count 207 cells/mm(3). A planned interim analysis demonstrated significantly lower treatment and virological responses with the NRTI-sparing strategy, resulting in premature study termination on 19 July 2005. The proportion of patients who remained on their assigned treatment strategy and had pVL <50 copies/mL on the NRTI-sparing regimen was 60.0%, compared with 82.5% on the NRTI-containing regimen at W24 (P = 0.009) and 66.7% and 82.5%, respectively, at W48 (P = 0.059). Treatment failure was associated with the NRTI-sparing strategy in patients with suboptimal adherence and with being from sub-Saharan Africa. No differences in fat distribution were noted. CONCLUSIONS An initial NRTI-sparing regimen is less successful and virologically less potent than standard NRTI-containing regimen and should not therefore be used as the first line of treatment.
Role of metabotropic glutamate (ACPD) receptors at the parallel fiber-Purkinje cell synapse.

1. The role of metabotropic glutamate receptors at the parallel fiber (PF)-Purkinje cell synapse in cerebellum was studied by examining the actions of the active stereoisomer (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [1S,3R-ACPD (25-50 microM)] on fura-2-loaded, patch-clamped rat Purkinje cells in thin slices. 2. The bath application of 1S,3R-ACPD evoked a direct post-synaptic depolarization that readily desensitized during prolonged (> 1 min) applications of the drug. This depolarizing response to 1S,3R-ACPD differed from the slow depolarization to 1S,3R-ACPD observed in cortical neurons mediated via closure of potassium channels in that it was not associated with an obvious change in membrane conductance and was not blocked by external barium. Similarly, slow inward rectifier currents were not affected during the 1S,3R-ACPD-induced depolarization. 3. The direct depolarization induced by 1S,3R-ACPD was not mediated by N-methyl-D-aspartate (NMDA) or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid kainate (AMPA)-KA excitatory amino acid (EAA) receptor subtypes, because the response was not blocked in the presence of antagonists of these receptors. 4. The EAA antagonist L-2-amino-3-phosphonopropionic acid, which blocks 1S,3R-ACPD-induced inositide synthesis in other cell types, had no effect on the depolarizing response. 5. Fura-2 measurements of somatic [Ca2+]i revealed that [Ca2+]i was not elevated during the 1S,3R-ACPD-induced depolarization unless the cell fired calcium-dependent action potentials. 6. In addition to the direct depolarization induced by 1S,3R-ACPD, the amplitude of PF-evoked excitatory postsynaptic potentials (EPSPs) was profoundly and reversibly reduced. This effect was observed in all cells regardless of whether a direct depolarization was produced by 1S,3R-ACPD. This reduction of the PF EPSP generally preceded the onset of depolarizing responses, did not desensitize during prolonged applications of 1S,3R-ACPD, and was reversible. 7. The reversible reduction of the PF EPSP by 1S,3R-ACPD was not related to a postsynaptic blocking action of the drug, because responses of Purkinje cells to AMPA, an agonist of the EAA receptor subtype mediating the EPSP, were reversibly potentiated in the presence of 1S,3R-ACPD. 8. The nitric oxide synthesis promoter sodium nitroprusside (1-3 nM) had no effect on the amplitude of PF EPSP or the membrane properties of Purkinje cells. (ABSTRACT TRUNCATED AT 400 WORDS)
myGrid: personalised bioinformatics on the information grid

MOTIVATION The (my)Grid project aims to exploit Grid technology, with an emphasis on the Information Grid, and provide middleware layers that make it appropriate for the needs of bioinformatics. (my)Grid is building high level services for data and application integration such as resource discovery, workflow enactment and distributed query processing. Additional services are provided to support the scientific method and best practice found at the bench but often neglected at the workstation, notably provenance management, change notification and personalisation. RESULTS We give an overview of these services and their metadata. In particular, semantically rich metadata expressed using ontologies necessary to discover, select and compose services into dynamic workflows.
Evolution of Xylan Substitution Patterns in Gymnosperms and Angiosperms: Implications for Xylan Interaction with Cellulose1[CC-BY]

The xylan decoration pattern in all lineages of gymnosperms permits hydrogen bonding of xylan to cellulose. The interaction between cellulose and xylan is important for the load-bearing secondary cell wall of flowering plants. Based on the precise, evenly spaced pattern of acetyl and glucuronosyl (MeGlcA) xylan substitutions in eudicots, we recently proposed that an unsubstituted face of xylan in a 2-fold helical screw can hydrogen bond to the hydrophilic surfaces of cellulose microfibrils. In gymnosperm cell walls, any role for xylan is unclear, and glucomannan is thought to be the important cellulose-binding polysaccharide. Here, we analyzed xylan from the secondary cell walls of the four gymnosperm lineages (Conifer, Gingko, Cycad, and Gnetophyta). Conifer, Gingko, and Cycad xylan lacks acetylation but is modified by arabinose and MeGlcA. Interestingly, the arabinosyl substitutions are located two xylosyl residues from MeGlcA, which is itself placed precisely on every sixth xylosyl residue. Notably, the Gnetophyta xylan is more akin to early-branching angiosperms and eudicot xylan, lacking arabinose but possessing acetylation on alternate xylosyl residues. All these precise substitution patterns are compatible with gymnosperm xylan binding to hydrophilic surfaces of cellulose. Molecular dynamics simulations support the stable binding of 2-fold screw conifer xylan to the hydrophilic face of cellulose microfibrils. Moreover, the binding of multiple xylan chains to adjacent planes of the cellulose fibril stabilizes the interaction further. Our results show that the type of xylan substitution varies, but an even pattern of xylan substitution is maintained among vascular plants. This suggests that 2-fold screw xylan binds hydrophilic faces of cellulose in eudicots, early-branching angiosperm, and gymnosperm cell walls.
Associations of plasma n–3 polyunsaturated fatty acids with blood pressure and cardiovascular risk factors among Chinese

The relationship between plasma fatty acid (FA) levels and hypertension in Chinese is not fully understood. The aim of this study was to examine relationships between plasma phospholipid (PL) FAs and hypertension in Chinese subjects. One thousand one hundred and fifty-four subjects in Hangzhou, China, were recruited in this cross-sectional study. Two hundred and fourteen (160 males, 54 females) subjects with hypertension and 940 (664 males, 276 females) healthy subjects were identified. The prevalence of hypertension in females (19.6%) was significantly higher than that in males (16.4%). Compared with healthy subjects, hypertensive subjects showed significantly lower plasma PL 22:5n–3 (p = 0.017), 22:6n–3 (p = 0.008), PL polyunsaturated fatty acids (PUFAs; p < 0.001), n–3 PUFA (p = 0.015), n–6 PUFA (p < 0.001) and 20:4n–6 (p < 0.010). PL n–3 PUFA [odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.29–1.19] and n–3:n–6 (OR = 0.48, 95% CI = 0.12–1.86) were inversely associated with hypertension. However, plasma saturated fatty acid (SFA; OR = 2.01, 95% CI = 1.05–2.98) was significantly positively associated with hypertension. PL SFA was significantly positively associated with systolic blood pressure (p = 0.048), whereas plasma PL monounsaturated FA was significantly positively associated with diastolic blood pressure (DBP; p = 0.009) in hypertensive subjects. PL PUFA (p = 0.022) and n–3 PUFA (p = 0.047) were significantly negatively associated with DBP in hypertensive subjects. Our results suggest that plasma PL n–3 PUFA was significantly inversely associated with hypertension in Chinese. It would seem appropriate for hypertensive subjects to increase their dietary n–3 PUFA which may help reduce BP.
Simultaneous regulation of position and orientation for nonholonomic mobile robot

An image-based visual servoing control scheme is proposed for regulating the position and orientation of the nonholonomic mobile robot simultaneously based on an imprecisely calibrated camera. The proposed method only requires measurement information from image and utilizes the elements of the homography matrix between current and goal images to establish an error model, which is then used to develop an extended state observer (ESO)-based controller. Therein, two ESOs are designed to compensate for the parameter uncertainties of the error model. The mobile robot will be maneuvered to a desired configuration by the controller when the position and orientation errors are regulated to zero simultaneously. Global asymptotic convergent property of system errors is proven. Simulations validate the effectiveness of the proposed control scheme.
Divergent selection for shape of growth curve in Japanese quail. 3. Onset of sexual maturity and basic characteristics of early lay

1. The onset of lay, quality of eggs during early lay and gonadal development of both sexes were analysed in meat-type lines of Japanese quail, HG and LG divergently selected for high and low relative weight gain between 11 and 28 d of age, respectively, and constant body weight (BW) at 49 d of age. 2. The LG line was sexually mature at an earlier age and lower BW than the HG line. This corresponded with the trend during embryonic and early postnatal development. 3. Analysis of gonads also confirmed earlier sexual development in the LG than in the HG line. In both lines, the growth of testes was detected about one week earlier than the growth of ovary. 4. Despite the different age and BW at onset of lay, HG and LG quail commenced lay at the same degree of maturity (about 90% of adult BW). This implied that the onset of sexual maturity could be identified as a point on the growth curve which terminates the linear phase. 5. When compared with the LG line, the HG line was characterised by a longer acceleration and shorter retardation phase of the growth curve. This difference is seen as an important determinant of line differences in growth and reproductive performance.
Recurrent Psoriasis After Introduction of Belatacept in 2 Kidney Transplant Recipients

Organ transplant recipients may have skin diseases as a result of immunosuppression, but psoriasis is reported infrequently. This skin condition may be induced by immunosuppression imbalance. We present 2 cases of recurrent psoriasis in 2 kidney transplant patients with belatacept-based immunosuppressive regimens. Two years after transplant, upon suspicion of calcineurin inhibitor neurotoxicity in the first patient, tacrolimus was replaced with belatacept. The patient’s neurological signs resolved but the patient presented with skin lesions compatible with psoriatic plaques, successfully treated with betamethasone dipropionate and hydrocortisone. The second patient had a history of obesity and dyslipidemia, left foot amputation, and psoriasis. He received a kidney transplant, and maintenance immunosuppression included prednisone, mycophenolate mofetil, and belatacept. At posttransplant month 15, the patient presented with cutaneous erythematosus, maculopapular, and desquamative lesions compatible with psoriasis, treated with betamethasone dipropionate. The belatacept-based immunosuppressive regimens were maintained and psoriasis resolved. Psoriasis is a potential complication in kidney recipients that may recur when belatacept is used and/or tacrolimus is withdrawn as it could have happened in the first patient. The characteristics of the second case may suggest that belatacept might not have been the inciting agent. Good results were obtained with topical treatment.
A simple way to measure daily lifestyle regularity

A brief diary instrument to quantify daily lifestyle regularity (SRM‐5) is developed and compared with a much longer version of the instrument (SRM‐17) described and used previously. Three studies are described. In Study 1, SRM‐17 scores (2 weeks) were collected from a total of 293 healthy control subjects (both genders) aged between 19 and 92 years. Five items (1) Get out of bed, (2) First contact with another person, (3) Start work, housework or volunteer activities, (4) Have dinner, and (5) Go to bed were then selected from the 17 items and SRM‐5 scores calculated as if these five items were the only ones collected. Comparisons were made with SRM‐17 scores from the same subject‐weeks, looking at correlations between the two SRM measures, and the effects of age and gender on lifestyle regularity as measured by the two instruments. In Study 2 this process was repeated in a group of 27 subjects who were in remission from unipolar depression after treatment with psychotherapy and who completed SRM‐17 for at least 20 successive weeks. SRM‐5 and SRM‐17 scores were then correlated within an individual using time as the random variable, allowing an indication of how successful SRM‐5 was in tracking changes in lifestyle regularity (within an individual) over time. In Study 3 an SRM‐5 diary instrument was administered to 101 healthy control subjects (both genders, aged 20–59 years) for two successive weeks to obtain normative measures and to test for correlations with age and morningness. Measures of lifestyle regularity from SRM‐5 correlated quite well (about 0.8) with those from SRM‐17 both between subjects, and within‐subjects over time. As a detector of irregularity as defined by SRM‐17, the SRM‐5 instrument showed acceptable values of kappa (0.69), sensitivity (74%) and specificity (95%). There were, however, differences in mean level, with SRM‐5 scores being about 0.9 units [about one standard deviation (SD)] above SRM‐17 scores from the same subject‐weeks. SRM‐5 scores also deviated more from a Gaussian distribution than did SRM‐17 ones. In a study with a sample size of 101, the new SRM‐5 instrument yielded scores with a mean of 4.11 and an SD of 1.13. Correlations between lifestyle regularity and age, and between lifestyle regularity and morningness appeared similar whether 5‐item or 17‐item SRM measures were used. When a gender difference in lifestyle regularity appeared, it was detected by both SRM‐5 and SRM‐17 measures.
Safety and efficacy of nonvitamin K antagonist oral anticoagulants versus warfarin in diabetic patients with atrial fibrillation: A study‐level meta‐analysis of phase III randomized trials

In patients with atrial fibrillation (AF), the safety and efficacy of nonvitamin K antagonist oral anticoagulants (NOACs) vs warfarin according to diabetes mellitus (DM) status are not completely characterized. We performed a meta‐analysis to clarify whether in these patients the strategy of oral anticoagulation should be tailored to diabetes status. In this study‐level meta‐analysis, we included 4 randomized phase III trials comparing NOACs and warfarin in patients with nonvalvular AF; a total of 18 134 patients with DM and 40 454 without DM were overall considered. Incidence of the following outcome measures was evaluated during the follow‐up: stroke or systemic embolism, ischemic stroke, major bleeding, intracranial bleeding, and vascular death. Use of NOACs compared with warfarin reduced stroke/systemic embolism in diabetic (Risk Ratios [RR] 0.80, 95% CI 0.68‐0.93; P = .004) and nondiabetic patients (RR 0.83, 0.73‐0.93; P = .001) (P for interaction .72). No interaction between diabetes status and benefits of NOACs was found for the occurrence of ischemic stroke, major bleeding, or intracranial bleeding (P for interaction >.05 for each comparison). Reduction of vascular death rates with NOACs was significant in diabetic patients (4.97% vs 5.99% with warfarin; RR 0.83, 0.72‐0.96; P = .01), in whom absolute the reduction of this outcome measure was higher than in nondiabetics (1.02% vs 0.27%), although no interaction was present (P = .23). Results of this meta‐analysis support the safety and efficacy of NOACs compared with warfarin in diabetic patients with nonvalvular AF.
Differential modulation of rod and cone calcium currents in tiger salamander retina by D2 dopamine receptors and cAMP

Synaptic transmission from vertebrate photoreceptors involves activation of L‐type calcium currents (ICa). Dopamine is an important circadian neuromodulator in the retina and photoreceptors possess D2 dopamine receptors. We examined modulation of ICa by dopamine and cAMP in retinal slices and isolated cells of larval tiger salamander. Results show that dopamine and a D2 agonist, quinpirole, enhanced ICa in rods and red‐, blue‐ and UV‐sensitive small single cones but inhibited ICa in red‐sensitive large single cones. A D1 agonist, SKF‐38393, was without effect. Quinpirole effects were blocked by pertussis toxin (PTx) pretreatment indicating involvement of PTx‐sensitive G‐proteins. Like dopamine, inhibition of cAMP‐dependent protein kinase (PKA) by Rp‐cAMPS enhanced ICa in rods and small single cones, but inhibited ICa in large single cones. In contrast, forskolin and Sp‐cAMPS, which stimulate PKA, inhibited ICa in rods and small single cones but enhanced ICa in large single cones. Sp‐cAMPS also occluded effects of quinpirole. These results suggest that D2 receptors modulate ICa via inhibition of cAMP. Differences among the responses of photoreceptors to cAMP are consistent with the possibility that small single cones and rods may possess different Ca2+ channel subtypes than large single cones. The results with dopamine and quinpirole showing inhibition of ICa in large single cones and enhancement of rod ICa were unexpected because previous studies have shown that dopamine suppresses rod inputs and enhances cone inputs into second‐order neurons. The present results therefore indicate that the dopaminergic enhancement of cone inputs does not arise from modulation of photoreceptor ICa.
Survival outcome of care by specialist surgeons in breast cancer: a study of 3786 patients in the west of Scotland

Abstract Objective: To compare survival outcome for patients with breast cancer cared for by specialist and non-specialist surgeons in a geographically defined area. Design: Retrospective study of all female patients aged under 75 years in the area treated between 1980 and June 1988 (before breast screening began). Patients were identified from the cancer registry and from pathology records of all hospitals in the area. Specialist surgeons were identified by one author. All other surgeons caring for patients from the area were considered non-specialists. Setting: A geographically defined population in urban west of Scotland. Subjects: 3786 patients with histologically verified breast cancer operated on between 1 January 1980 and 30 June 1988 and followed to 31 December 1993. Main outcome measures: Five and 10 year survival rates for specialists and non-specialists; relative hazard ratios derived from Cox's proportional hazards model adjusted for prognostic factors—age, socioeconomic status, tumour size, and nodal involvement. Results: The five year survival rate was 9% higher and the 10 year survival 8% higher for patients cared for by specialist surgeons. A reduction in risk of dying of 16% (95% confidence interval 6% to 25%) was found after adjustment for age, tumour size, socioeconomic status, and nodal involvement. The benefit of specialist care was apparent for all age groups, for small and large tumours, and for tumours that did and did not affect the nodes and was consistent across all socioeconomic categories. Conclusions: Survival differences of the magnitude demonstrated have implications for the provision of services for the treatment of women with breast cancer. There is a need to improve equity in the treatment of breast cancer.