Miracle-dz/UniFAR-FTUs huggingface dataset:
Evidence That 2-Arachidonoylglycerol but Not N-Palmitoylethanolamine or Anandamide Is the Physiological Ligand for the Cannabinoid CB2 Receptor

We examined the effect of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, on the intracellular free Ca2+ concentrations in HL-60 cells that express the cannabinoid CB2 receptor. We found that 2-arachidonoylglycerol induces a rapid transient increase in intracellular free Ca2+concentrations in HL-60 cells. The response was affected by neither cyclooxygenase inhibitors nor lipoxygenase inhibitors, suggesting that arachidonic acid metabolites are not involved. Consistent with this notion, free arachidonic acid was devoid of any agonistic activity. Importantly, the Ca2+ transient induced by 2-arachidonoylglycerol was blocked by pretreatment of the cells with SR144528, a CB2 receptor-specific antagonist, but not with SR141716A, a CB1 receptor-specific antagonist, indicating the involvement of the CB2 receptor but not the CB1 receptor in this cellular response. Gi or Go is also assumed to be involved, because pertussis toxin treatment of the cells abolished the response. We further examined the structure-activity relationship. We found that 2-arachidonoylglycerol is the most potent compound among a number of naturally occurring cannabimimetic molecules. Interestingly, anandamide and N-palmitoylethanolamine, other putative endogenous ligands, were found to be a weak partial agonist and an inactive ligand, respectively. These results strongly suggest that the CB2 receptor is originally a 2-arachidonoylglycerol receptor, and 2-arachidonoylglycerol is the intrinsic natural ligand for the CB2 receptor that is abundant in the immune system.
Structured management strategy versus usual care for gastroesophageal reflux disease: rationale for pooled analysis of five European cluster-randomized trials

Background: Gastroesophageal reflux disease (GERD) has a major impact at the primary care level and there is a need to evaluate whether the diagnosis and therapeutic management of GERD in Europe needs to be improved. Methods: This project was designed to test the hypothesis that a new primary care management strategy would improve outcomes for patients with GERD, compared with usual care, in Europe. The analysis pools five separate cluster-randomized studies conducted in Austria, Italy, Norway, Spain and Sweden. These studies used a strategy based on the self-administered GerdQ questionnaire to stratify adult patients with symptoms of heartburn or regurgitation according to the frequency and impact of symptoms. A score of ≥8 indicates a high probability of suffering GERD. Patients with a GerdQ impact score ≤2 were treated with generic proton-pump inhibitors according to local guidance, and patients with an impact score ≥3 were treated with esomeprazole 40 mg once daily. Results: In total, 2400 patients were enrolled across the five studies. The protocols were modified by individual countries according to their local guidelines/requirements. In Norway, the new management strategy was compared with traditional routine endoscopy and 24-hour pH-metry, and encompassed proton-pump inhibitor reimbursement restrictions. Outcome measures differed by country, but included control of GERD symptoms, self-rated health status and work productivity, treatment changes, specialist referrals and physician adherence. GERD-related use of healthcare resources was also evaluated. Conclusion: The pooled analysis will determine whether a locally adapted primary care management strategy for GERD, using GerdQ as a patient-tailored diagnostic and therapeutic evaluation tool, is beneficial compared with usual care across five countries with different standard approaches to GERD management and control.
Immune Deficiency and Risk for Malignancy Among Persons with AIDS

Background People with AIDS have an elevated risk for cancer. We studied the relationship between cancer risk and AIDS-related immunosuppression as measured by CD4 count at AIDS onset. Methods We linked records from AIDS and cancer registries in 11 US regions (1990–1996). We studied 82,217 (86.6%) adults who had a CD4 count measured at AIDS onset and survived into the follow-up period. We calculated standardized incidence ratios (SIRs) for AIDS-defining (Kaposi sarcoma [KS], non-Hodgkin lymphoma [NHL] and cervical cancer) as well as non-AIDS-defining cancers in the 2 years after AIDS onset. For each cancer, the change in SIRs across CD4 counts (0–49 cells/mm3, 50–99 cells/mm3, 100–199 cells/mm3, and ≥200 cells/mm3) was modeled using Poisson regression. Results The SIRs for KS, NHL, and cervical cancer were 258, 78, and 8.8, respectively. For each fall of 100 CD4 cells/mm3, RRs were 1.36 (95% CI: 1.29–1.43) for KS and 1.48 (95% CI: 1.37–1.59) for NHL. Among NHL subtypes, the association with lower CD4 counts was strongest for immunoblastic lymphoma (RR =1.64, 95% CI: 1.37–1.96, per decline of 100 CD4 cells/mm3) and central nervous system lymphoma (RR = 2.29, 95% CI: 1.95–2.69). The SIR for cervical cancer did not vary with CD4 count (p = .74). For non-AIDS-defining cancers (overall SIR = 2.1), neither the combined risk nor the risk of specific types was associated with declining CD4 counts. Conclusions KS and NHL risk increased with level of immunosuppression at AIDS onset. Risks for other cancers, including cervical cancer, were unrelated to CD4 counts. Elevated risks for non-AIDS cancers may be a result of lifestyle factors.
Transient response of aerobic and anoxic activated sludge activities to sudden substrate concentration changes

The state‐of‐the‐art understanding of activated sludge processes as summarized in activated sludge models (ASMs) predicts an instantaneous increase in the biomass activity (which is measured, e.g., by the corresponding respiration rate OUR, NUR, etc.) under sudden substrate concentration changes. Experimental data (e.g., short‐term batch respiration experiments under aerobic or anoxic conditions) collected for the calibration of the dynamic models (ASMs) often exhibit a transient phenomenon while attaining maximum activity, which cannot be explained by the current understanding of the activated sludge process. That transient phenomenon exhibits itself immediately upon addition of a substrate source to an endogenously respiring activated sludge sample and it usually takes a few minutes until the activated sludge reaches its maximum possible rate under given environmental conditions. This discrepancy between the state‐of‐the‐art model and the experimental data is addressed in detail in this investigation. It is shown that the discrepancy is not caused by an error in the experimental set‐up/data but it is rather due to model inadequacy. Among the hypotheses proposed, it appears that this transient response of the activated sludge most likely results from the sequence of intracellular reactions involved in substrate degradation by the activated sludge. Results from studies performed elsewhere with pure cultures (S. cerevisae and E. coli) support the hypothesis. The transient phenomenon can be described by a dynamic metabolic network model or by a simple first‐order model, as adopted in this study. The transient phenomenon occurring in short‐term batch respiration experiments is shown to interfere severely with parameter estimation if not modeled properly (2.8%, 11.5%, and 16.8% relative errors [average of three experiments] on YH, μmaxH, and KS, respectively). Proper modeling of this transient phenomenon whose time constant is on the order of minutes (1 to 3 min) is expected to contribute fundamentally to a better understanding and modeling of Orbal, carousel, and SBR‐type treatment plants with fast‐alternating process conditions, although such studies are beyond the scope of this report. © 2004 Wiley Periodicals, Inc.
Effect of Passive Smoking on the Growth of Pulmonary Function and Respiratory Symptoms in Schoolchildren.

BACKGROUND Environmental tobacco smoke affects the current and future health of children. OBJECTIVE To determine whether schoolchildren aged 8-17 years old residing at an altitude of 2,240 m and exposed to tobacco smoke at home presented a reduction in the growth of pulmonary function and a greater problem of respiratory symptoms and infections compared with non-exposed children. MATERIALS AND METHODS We followed, with questionnaires and spirometry, 1,632 boys and 1,555 girls from Mexico City and its metropolitan area (the Metropolitan Study to Evaluate the Chronic Effects of Pollution in School-age Children [EMPECE]) every six months for six years. The impact of passive smoking was estimated by mixed-effects models and Generalized Linear and Latent Mixed Models (GLLAMM), stratifying by gender and adjusting for age, height, weight, and ozone levels. RESULTS Passive smoking (reported by one-half of participants) was associated with reduced spirometric lung function (log transformed or as Z-scores) and a higher frequency of self-reported respiratory symptoms and respiratory infections. Levels of forced expiratory volume in 1 second and forced vital capacity in individuals exposed to passive smoking were 6.8 and 14.1 ml, respectively, below those of non-exposed children, and these values decreased with increasing number of smokers at home and higher ozone levels. CONCLUSIONS Passive smoking in children is a significant risk factor for respiratory disease and reduced lung function growth, which are additive with levels of air pollution, asthma, and the presence of respiratory symptoms.
Multimedia streaming using partially reliable concurrent multipath transfer for multihomed networks

The authors propose a partially reliable-concurrent multipath transfer (PR-CMT) protocol for multimedia streaming. The novelty of PR-CMT is to combine techniques of CMT's concurrent multipath transfer, PR-SCTP's partially reliable transmission and prioritised stream transmission. Moving picture experts group (MPEG) frames are with varying priorities and lifetime. PR-CMT can transmit important frames before other frames but does not transmit lifetime expired frames. The combination of the aforementioned techniques, however, causes imprecise congestion window and receiver buffer blocking problems without suitable control. Consequently, the throughput and video quality degrade. PR-CMT adopts the concept of delay abandoning data to resolve the imprecise cwnd and the receiver buffer blocking problems. The simulation results show that PR-CMT can precisely infer cwnd. Most importantly, PR-CMT can prevent large gaps between two playable frames to have good video quality.
Next Generation IGBT and Package Technologies for High Voltage Applications

In this paper, we will present an overview of the latest results covering both Insulated Gate Bipolar Transistor (IGBT) and packaging technologies intended for demanding high-power applications. We will present the recently developed press pack module rated at 4500 V and 3000 A utilizing an advanced reverse conducting RC-IGBT for hard switching application, which together with the improved module layout yields the most powerful IGBT-based device up to date. For applications that require isolated modules, we will show our new dual IGBT module rated up to 3.3 kV and 450 A. The module layout was optimized to allow highly scalable converter designs with overall low stray inductances. This opens up new possibilities to further reduce losses due to the fact that the devices can be made thinner than today’s limits for achieving lower switching losses with soft performance. We will show the latest results from the enhanced trench IGBT-cell development and give an outlook for the power levels that can be achieved by combining the new cell with the RC-IGBT concept.
Sex Differences in Glucocorticoid Sensitivity of Proinflammatory Cytokine Production After Psychosocial Stress

Objective Men and women show marked differences in susceptibility to disorders related to the immune system. These gender differences have been proposed to be mediated by functional interactions of the hypothalamus-pituitary-adrenal (HPA) and hypothalamus-pituitary-gonadal (HPG) axes. A potential mechanism involved in this interaction is the glucocorticoid (GC) sensitivity of relevant target tissues for GC. Therefore, the aim of the study reported here was to investigate the impact of psychosocial stress and HPA axis activation on the GC sensitivity of proinflammatory cytokine production in men and women. Methods A total of 45 healthy subjects were investigated. Eighteen women in the luteal phase of their menstrual cycle and 27 men were exposed to a psychosocial stress test (Trier Social Stress Test). Salivary free cortisol levels were measured repeatedly after exposure to the stressor. GC sensitivity was assessed in vitro by dexamethasone inhibition of lipopolysaccharide-stimulated production of interleukin-6 and tumor necrosis factor-&agr;. Results The stress test induced significant increases in salivary free cortisol with no significant differences between men and women. In contrast, GC sensitivity and lipopolysaccharide-stimulated cytokine production showed large gender differences. In men GC sensitivity was markedly increased 1 hour after stress, whereas GC sensitivity decreased significantly in women. Similarly, lipopolysaccharide-induced cytokine production decreased in response to stress in men but increased in women. Conclusions These results demonstrate that despite similar free cortisol responses of men and women (studied in the luteal phase) to psychosocial stress, gender may exert differential effects on the immune system by modulating GC sensitivity of proinflammatory cytokine production.
Gating of the CFTR Cl− channel by ATP‐driven nucleotide‐binding domain dimerisation

The cystic fibrosis transmembrane conductance regulator (CFTR) plays a fundamental role in fluid and electrolyte transport across epithelial tissues. Based on its structure, function and regulation, CFTR is an ATP‐binding cassette (ABC) transporter. These transporters are assembled from two membrane‐spanning domains (MSDs) and two nucleotide‐binding domains (NBDs). In the vast majority of ABC transporters, the NBDs form a common engine that utilises the energy of ATP hydrolysis to pump a wide spectrum of substrates through diverse transmembrane pathways formed by the MSDs. By contrast, in CFTR the MSDs form a pathway for passive anion flow that is gated by cycles of ATP binding and hydrolysis by the NBDs. Here, we consider how the interaction of ATP with two ATP‐binding sites, formed by the NBDs, powers conformational changes in CFTR structure to gate the channel pore. We explore how conserved sequences from both NBDs form ATP‐binding sites at the interface of an NBD dimer and highlight the distinct roles that each binding site plays during the gating cycle. Knowledge of how ATP gates the CFTR Cl− channel is critical for understanding CFTR's physiological role, its malfunction in disease and the mechanism of action of small molecules that modulate CFTR channel gating.
[Efficacy and safety of a reduced-dose of stavudine in HIV-infected patients under immunological and virological stable conditions].

BACKGROUND AND OBJECTIVE Stavudine (d4T) has shown a favourable short and long-term tolerability profile. Nevertheless, its usage is currently decreasing due to some safety concerns. We aimed to evaluate the efficacy and safety of d4T low-dose-based regimens. PATIENTS AND METHOD This was a multicenter and retrospective review chart of patients receiving standard doses of d4T for > or = 6 months (weight > 60 kg: 40 mg/12 h; weight < 60 kg: 30 mg/12 h) and having undetectable viral load for at least 3 months before the d4T dose reduction (weight > 60 kg: 30 mg/12 h; weight < 60 kg: 20 mg/12 h). Immunological and viral parametres, lipid profile and side effects were determined. RESULTS A total of 982 patients were included. The main reason for reducing the dose was prevention of toxicity (76%). After 6 months of follow-up, 97% and 84% patients had less than 400 and 50 cp/ml, respectively, and the CD4 cell count increased by 38 cel/ml. Lipids, lipodystrophy and peripheral polineuropathy improved but there was no statistical significance. CONCLUSIONS A d4T dose reduction in an immuno-virologically stable population does not affect treatment efficacy. Longer follow-ups are required to confirm improvements in the safety profile.
Mammalian P2X7 receptor pharmacology: comparison of recombinant mouse, rat and human P2X7 receptors

Background and purpose: Acute activation of P2X7 receptors rapidly opens a non‐selective cation channel. Sustained P2X7 receptor activation leads to the formation of cytolytic pores, mediated by downstream recruitment of hemichannels to the cell surface. Species‐ and single‐nucleotide polymorphism‐mediated differences in P2X7 receptor activation have been reported that complicate understanding of the physiological role of P2X7 receptors. Studies were conducted to determine pharmacological differences between human, rat and mouse P2X7 receptors.
From corners to rectangles — Directional road sign detection using learned corner representations

In this work we adopt a novel approach for the detection of rectangular directional road signs in single frames captured from a moving car. These signs exhibit wide variations in sizes and aspect ratios and may contain arbitrary information, thus making their detection a challenging task with applications in traffic sign recognition systems and vision-based localization. Our proposed approach was originally presented for additional traffic sign detection in small image regions and is generalized to full image frames in this work. Sign corner areas are detected by four ACF-detectors (Aggregated Channel Features) on a single scale. The resulting corner detections are subsequently used to generate quadrangle hypotheses, followed by an aggressive pruning strategy. A comparative evaluation on a database of 1500 German road signs shows that our proposed detector outperforms other methods significantly at close to real-time runtimes and yields thrice the very low error-rate of the recent MS-CNN framework while being two orders of magnitude faster.
HIV infection reveals widespread expansion of novel centromeric human endogenous retroviruses

Human endogenous retroviruses (HERVs) make up 8% of the human genome. The HERV-K (HML-2) family is the most recent group of these viruses to have inserted into the genome, and we have detected the activation of HERV-K (HML-2) proviruses in the blood of patients with HIV-1 infection. We report that HIV-1 infection activates expression of a novel HERV-K (HML-2) provirus, termed K111, present in multiple copies in the centromeres of chromosomes throughout the human genome yet not annotated in the most recent human genome assembly. Infection with HIV-1 or stimulation with the HIV-1 Tat protein leads to the activation of K111 proviruses. K111 is present as a single copy in the genome of the chimpanzee, yet K111 is not found in the genomes of other primates. Remarkably, K111 proviruses appear in the genomes of the extinct Neanderthal and Denisovan, while modern humans have at least 100 K111 proviruses spread across the centromeres of 15 chromosomes. Our studies suggest that the progenitor K111 integrated before the Homo-Pan divergence and expanded in copy number during the evolution of hominins, perhaps by recombination. The expansion of K111 provides sequence evidence suggesting that recombination between the centromeres of various chromosomes took place during the evolution of humans. K111 proviruses show significant sequence variations in each individual centromere, which may serve as markers in future efforts to annotate human centromere sequences. Further, this work is an example of the potential to discover previously unknown genomic sequences through the analysis of nucleic acids found in the blood of patients.
Human endothelial nitric oxide synthase gene transfer inhibits vascular smooth muscle cell proliferation and neointima formation after balloon injury in rats.

BACKGROUND Loss of endothelial NO production after arterial injury may contribute to restenosis, characterized by neointima formation and elastic recoil. Adenovirus-mediated transfer of the gene encoding NO synthase (NOS) in balloon-injured arteries may restore NO production and inhibit neointima formation. METHODS AND RESULTS After balloon injury, rat carotid arteries were transduced with 3x10(10) pfu/mL recombinant adenovirus carrying the human endothelial constitutive NOS cDNA (AdCMVceNOS, n=8) or no cDNA (AdRR5, n=8). ceNOS expression was confirmed by immunoblot analysis of vascular extracts and was localized by immunostaining in 30% of medial smooth muscle cells (SMCs) and in the adventitia of AdCMVceNOS-transduced arteries. Vascular cGMP levels were reduced from 3.9 pmol/g wet wt in uninjured arteries to 0.7 pmol cGMP/g after AdRR5 but were restored after ceNOS gene transfer (3.8 pmol cGMP/g wet wt, P<.05 versus AdRR5). Intima-to-media ratio 2 weeks after injury was significantly reduced (0.19+/-0.02 in AdCMVceNOS-infected versus 0.69+/-0.07 in AdRR5-infected arteries, P<.05). In vitro, BrdU incorporation of AdCMVceNOS-infected SMCs was reduced by 28% compared with AdRR5-infected SMCs. Transduced cells from injured carotid arteries subjected to FACS sorting showed a significantly lower BrdU labeling index in ceNOS-infected rats (29+/-6% versus 43+/-5% and 45+/-4% in control, injured, and AdRR5-infected rats, respectively, P<.05). CONCLUSIONS AdCMVceNOS gene transfer to balloon-injured rat carotid arteries restores vascular NO production and reduces neointima formation, at least in part because of an antiproliferative effect on medial SMCs. Adenovirus-mediated ceNOS gene transfer might reduce arterial restenosis after balloon angioplasty.
Maternal Request for In-hospital Supplementation of Healthy Breastfed Infants among Low-income Women

Background: While hospital policies and medical issues are important factors in determining exclusive breastfeeding rates, medically unnecessary supplementation of infants is likely to be due, in part, to maternal request for formula. Objectives: The goal of this project was to gain an understanding of the facilitating factors and decision-making processes surrounding maternal request for formula in the early postpartum period. Methods: A series of 12 focus groups were conducted among 97 English- and Spanish-speaking low-income participants in California’s Supplementary Nutrition Program for Women, Infants, and Children (WIC). Mothers were asked to share their in-hospital infant-feeding experiences. Results: The overarching theme that emerged was “lack of preparation” for what the early postpartum period would be like. Specifically, the decisions to formula feed fell into the following categories: inadequate preparation for newborn care (the need for rest and unrealistic expectations about infant behavior), lack of preparation for the process of breastfeeding, and formula as a solution to breastfeeding problems. Cultural factors were not mentioned as reasons for supplementation. Conclusion: Interventions to promote in-hospital exclusive breastfeeding must address mothers’ real and perceived barriers, specifically mothers’ expectations related to breastfeeding and infant behavior.