Miracle-dz/UniFAR-FTUs huggingface dataset:
Advances in immobilized artificial membrane (IAM) chromatography for novel drug discovery

ABSTRACT Introduction: The development of immobilized artificial membrane (IAM) chromatography has unfolded new perspectives for the use of chromatographic techniques in drug discovery, combining simulation of the environment of cell membranes with rapid measurements. Areas Covered: The present review describes the characteristics of phosphatidylcholine-based stationary phases and analyses the molecular factors governing IAM retention in comparison to n-octanol-water and liposomes partitioning systems as well as to reversed phase chromatography. Other biomimetic stationary phases are also briefly discussed. The potential of IAM chromatography to model permeability through the main physiological barriers and drug membrane interactions is outlined. Further applications to calculate complex pharmacokinetic properties, related to tissue binding, and to screen drug candidates for phospholipidosis, as well as to estimate cell accumulation/retention are surveyed. Expert opinion: The ambivalent nature of IAM chromatography, as a border case between passive diffusion and binding, defines its multiple potential applications. However, despite its successful performance in many permeability and drug-membrane interactions studies, IAM chromatography is still used as a supportive and not a stand-alone technique. Further studies looking at IAM chromatography in different biological processes are still required if this technique is to have a more focused and consistent application in drug discovery.
Local and systemic tolerability of a 2′O-methoxyethyl antisense oligonucleotide targeting interleukin-4 receptor-α delivery by inhalation in mouse and monkey

Abstract Antisense oligonucleotides (ASOs) bind and facilitate degradation of RNA and inhibit protein expression in pathways not easily targeted with small molecules or antibodies. Interleukin (IL)-4 and IL-13 potentiate signaling through the shared IL-4 receptor-α (IL-4Rα) subunit of their receptors. ASO targeting of IL-4Rα mRNA in a mouse model of asthma led to attenuation of airway hyperactivity, demonstrating potential benefit in asthma patients. This study focused on tolerability of inhaled IL-4Rα-targeting ASOs. Toxicity studies were performed with mouse- (ISIS 23189) and human-specific (ISIS 369645) sequences administered by inhalation. Four week (monkey) or 13 week (mouse) repeat doses at levels of up to 15 mg/kg/exposure (exp) and 50 mg/kg/exp, respectively, demonstrated dose-dependent effects limited to increases in macrophage size and number in lung and tracheobronchial lymph nodes. The changes were largely non-specific, reflecting adaptive responses that occur during active exposure and deposition of ASO and other material in the lung. Reversibility was observed at a rate consistent with the kinetics of tissue clearance of ASO. Systemic bioavailability was minimal, and no systemic toxicity was observed at exposure levels appreciably above pharmacological doses and doses proposed for clinical trials.
Detection Limits for Blood on Fabrics Using Attenuated Total Reflection Fourier Transform Infrared (ATR FT-IR) Spectroscopy and Derivative Processing

Attenuated total reflection Fourier transform infrared spectroscopy (ATR FT-IR) was used to detect blood stains based on signature protein absorption in the mid-IR region, where intensity changes in the spectrum can be related to blood concentration. Partial least squares regression (PLSR) was applied for multivariate calibrations of IR spectra of blood dilutions on four types of fabric (acrylic, nylon, polyester, and cotton). Gap derivatives (GDs) were applied as a preprocessing technique to optimize the performance of calibration models. We report a much improved IR detection limit (DL) for blood on cotton (2700× in dilution factor units) and the first IR DL reported for blood on nylon (250×). Due to sample heterogeneity caused by fabric hydrophobicity, acrylic fabric produced variable ATR FT-IR spectra that caused poor DLs in concentration units compared to previous work. Polyester showed a similar problem at low blood concentrations that lead to a relatively poor DL as well. However, the increased surface sensitivity and decreased penetration depth of ATR FT-IR make it an excellent choice for detection of small quantities of blood on the front surface of all fabrics tested (0.0010 µg for cotton, 0.0077 µg for nylon, 0.011 µg for acrylic, and 0.0066 µg for polyester).
The role of pentostatin in the treatment of T-cell malignancies: analysis of response rate in 145 patients according to disease subtype.

PURPOSE To assess the results of treatment with the purine analog 2'deoxycoformycin (pentostatin [DCF]) in patients with postthymic T-cell malignancies. PATIENTS AND METHODS One hundred forty-five patients with postthymic T-cell malignancies were given DCF intravenously at 4 mg/m2/wk for the first 4 weeks and then every 2 weeks until maximal response; the last 30 patients received weekly injections until maximal response. RESULTS The overall response rate was 32% (complete responses [CRs] plus partial responses [PRs]), with marked variation according to diagnosis. The best responses occurred in patients with Sézary syndrome (62%) and T-prolymphocytic leukemia (T-PLL) (45%), with CRs in three of 16 Sézary syndrome and five of 55 T-PLL patients. In contrast, no responses (NRs) were documented in 13 patients with other types of cutaneous T-cell lymphoma, including five mycosis fungoides. Two of five patients with large granular lymphocyte (LGL) leukemia had a CR and two of four with Sézary cell leukaemia had a PR. A low response rate was observed in 27 patients with peripheral T-non-Hodgkin's lymphoma (T-NHL) (19%) and in 25 with adult T-cell leukemia/lymphoma (ATLL) (12%). The latter included two CRs and one PR. Toxicity was low and DCF was generally well tolerated. No significant differences were observed when results were analyzed according to previous treatment. Disease subtype was the most important factor to influence results. CONCLUSION We conclude that DCF is effective as a single agent in T-PLL, Sézary syndrome, and LGL leukemia, but has low activity in other T-cell disorders.
Use of DInSAR techniques for the assessment of tide gauge measurements for long term past sea level evolution estimation reliability

Before the satellite altimetry era, tide gauges are the unique source of information to monitor global sea level rise due to anthropogenic climate change. As sea level changes display regional variability, its global mean can be estimated by averaging trends from good quality tide gauge. This leads to sea level rise rates of 1.65 +/- 0.2 mm/yr during the 20th century. However, this value and the related uncertainties are subject to discussion: 1. the network of available tide gauges is distributed in an uneven way: most of datasets available cover the Northern hemisphere, whereas previous studies suggest that sea level rise has been different in the northern and southern hemispheres. 2. over the altimetry era (1992-present), the sea level budget can be estimated by summing each contributing factor (mountain glaciers, ice sheets, thermosteric effects, land water storage), within uncertainties reaching 10 to 15% for each component. The same validation is more difficult for the recent period, because less data are available, thus questioning again the precise rate of mean sea level over the 20th century.
Tobacco smoke regulates the expression and activity of microsomal prostaglandin E synthase‐1: role of prostacyclin and NADPH‐oxidase

Tobacco smoke (TS) interacts with interleukin‐1β (IL‐1β) to modulate generation of reactive oxygen species (ROS) and expression of cyclooxygenase‐2. We explored molecular mechanisms by which TS/IL‐1β alters expression and activity of microsomal‐prostaglandin E synthase‐1 (mPGES‐1) and of prostacyclin synthase (PGIS) in mouse cardiac endothelial cells. TS (EC50 ~5 puffs/L) interacting with IL‐1β (2 μg/L) up‐regulates PGE2 production and mPGES‐1 expression, reaching a plateau at 4–6 h, but down‐regulates prostacyclin (PGI2) release by increasing IL‐1β‐mediated PGIS tyrosine nitration. Inhibition of NADPH‐oxidase, achieved pharmacologically and/or by silencing its catalytic subunit p47phox, or exogenous PGI2 (carbaprostacyclin; IC50 ~5 μM) prevents production of both ROS and PGE2, and negatively modulates mPGES‐1 expression induced by TS/IL‐1β. Moreover, inhibiting PGI2, either using PGIS siRNA and/or CAY10441 (EC50 ~20 nM), a PGI2 receptor antagonist, increases NADPH‐oxidase activation, mPGES‐1 synthesis, and PGE2 production. Finally, lower PGI2 levels associated with higher PGIS tyrosine nitration, p47phox translocation to the membrane (an index of activation of NADPH‐oxidase), and mPGES‐1 expression and activity were detected in cardiovascular tissues of ApoE–/– mice exposed to cigarette smoke compared to control mice. In conclusion, cigarette smoke in association with cytokines alters the balance between PGI2/PGE2, reducing PGI2 production and increasing synthesis and activity of mPGES‐1 via NADPH‐oxidase activation, predisposing to development of pathological conditions. —Barbieri, S. S. , Amadio, P., Gianellini, S. , Zacchi, E. , Weksler, B. B. , Tremoli, E. Tobacco smoke regulates the expression and activity of microsomal prostaglandin E synthase‐1: role of prostacyclin and NADPH‐oxidase. FASEB J. 25, 3731–3740 (2011). www.fasebj. org
How are thiopurines used and monitored by Swedish gastroenterologists when treating patients with inflammatory bowel disease?

Abstract Objective. To perform a survey of thiopurine treatment in inflammatory bowel disease (IBD) among Swedish gastroenterologists. Material and methods. A web-based questionnaire consisting of 25 multiple-choice questions was sent to 322 gastroenterologists in adult practice. Results. A total of 132 questionnaires were received giving a response rate of 41%. Thiopurines were used by all 122 gastroenterologists in IBD practice and azathioprine was the first-choice thiopurine among 118 (97%) of them. Almost all gastroenterologists (97%) used weight-based dosing that was gradually escalated. The vast majority (89%) considered that efficacy should be evaluated within 6 months of therapy, while opinions regarding the optimal duration of therapy varied considerably. It was seen that 74% switched thiopurine in case of intolerance to the first-line substance. Thiopurine S-methyltransferase (TPMT) determinations were performed by 74% of the gastroenterologists and 67% used metabolite measurements. TPMT analyzers were more likely to measure metabolites (74 vs. 43%, p = 0.002). A quarter of the respondents were familiar with unconventional immunomodulation (co-administration of allopurinol, 6-thioguanine, mycophenolate mofetil or tacrolimus) and these respondents were also more likely to measure metabolites (79 vs. 52%; p = 0.002). Conclusions. Thiopurines are well established in the treatment of IBD among Swedish gastroenterologists. New and evolving knowledge about thiopurine therapy in IBD has been adapted to a large extent. Whether this change in clinical practice will have an impact on treatment outcomes has yet to be proven.
Racial differences and the role of neighborhood in the sequencing of marijuana and tobacco initiation among urban youth

Background: With patterns of initiation of tobacco and marijuana changing, there is increasing evidence that marijuana use may serve as an antecedent to tobacco use among adolescents. However, studies have not fully characterized the prevalence of these patterns among vulnerable youth and have rarely examined the factors that predict the sequencing of onset of tobacco and marijuana use. Methods: Utilizing longitudinal data from a sample of urban youth followed from age 6 to age 18, the authors identify the sequencing of initiation of tobacco and marijuana and test whether race and 5 neighborhood factors (i.e., perceived disorder, drug activity, drug access, exposure to violence, and exposure to violent victimization) predict onset sequencing. Results: Various sequencing patterns were observed, with 12.4% of the sample initiating marijuana use before tobacco use was initiated. In adjusted logistic regression models, black youth were 2.66 times as likely as whites to initiate marijuana before tobacco compared with initiating tobacco before marijuana (P = .032). Youth with greater exposure to violent victimization were 3.89 times as likely to initiate marijuana first than initiate tobacco first (P = .002). Other neighborhood factors were not statistically significantly associated with sequencing. Conclusions: Black youth and youth with greater exposure to victimization had an increased risk of initiating marijuana before tobacco, which suggests that this pattern may be rooted in specific risk factors. Substance use prevention efforts should consider taking into account that marijuana use may put certain youth at risk of initiating tobacco. Future research needs to monitor sequencing, as well as risk factors for and consequences of the various patterns, particularly since marijuana use and the mixing of tobacco and marijuana use are gaining acceptability in general populations.
An Architecture for a Dependable Distributed Sensor System

In future smart environments, mobile applications will find a dynamically varying number of networked sensors that offer their measurement data. This additional information supports mobile applications in operating faster, with a higher precision and enhanced safety. The potentially increased redundancy obtained in such scenarios, however, is seriously affected by additional uncertainties as well. First, the dependence on wireless communication introduces new latencies and faults, as well as errors, and second, sensors of the environment may be disturbed, of low quality, or even faulty. The quality of the collected data therefore has to be dynamically assessed. Our work aims to provide a generic programming abstraction for fault-tolerant sensors and fusion nodes that cope with varying quality of measurements and communication.
Rotary Suspension Culture Enhances the Efficiency, Yield, and Homogeneity of Embryoid Body Differentiation

Embryonic stem (ES) cells hold great promise as a robust cell source for cell‐based therapies and as a model of early embryonic development. Current experimental methods for differentiation of ES cells via embryoid body (EB) formation are either inherently incapable of larger‐scale production or exhibit limited control over cell aggregation during EB formation and subsequent EB agglomeration. This report describes and characterizes a novel method for formation of EBs using rotary orbital motion that simultaneously addresses both concerns. EBs formed under rotary suspension conditions were compared with hanging‐drop and static EBs for efficiency of EB formation, cell and EB yield, homogeneity of EB size and shape, and gene expression. A 20‐fold enhancement in the number of cells incorporated into primitive EBs in rotary versus static conditions was detected after the first 12 hours, and a fourfold increase in total cell yield was achieved by rotary culture after 7 days. Morphometric analysis of EBs demonstrated formation and maintenance of a more uniform EB population under rotary conditions compared with hanging‐drop and static conditions. Quantitative gene expression analysis indicated that rotary EBs differentiated normally, on the basis of expression of ectoderm, endoderm, and mesoderm markers. Increased levels of endoderm gene expression, along with cystic EB formation, indicated by histological examination, suggested that differentiation was accelerated in rotary EBs. Thus, the rotary suspension culture method can produce a highly uniform population of efficiently differentiating EBs in large quantities in a manner that can be easily implemented by basic research laboratories conducting ES cell differentiation studies.
Role of amino acids in translational mechanisms governing milk protein synthesis in murine and ruminant mammary epithelial cells

The role of amino acids (AA) on translational regulation in mammary epithelial cells cultured under lactogenic conditions was studied. The rates of total protein synthesis and β‐lactoglobulin (BLG) synthesis in mouse CID‐9 cells were 2.1‐ or 3.1‐fold higher, respectively, than in their bovine L‐1 counterparts. Total AA deprivation or selective deprivation of Leu had a negative protein‐specific effect on BLG synthesis that was more pronounced in bovine cells than in murine cells. Dephosphorylation of eukaryotic initiation factor 4E‐binding protein 1 (4E‐BP1) and S6 kinase (S6K1) on Thr389 but not on Ser411 was also more prominent in bovine cells. Noteably, deprivation of Leu had a less marked effect on BLG synthesis and 4E‐BP1 or S6K1 phosphorylation than deprivation of all AA. In AA‐deprived CID‐9 cells, Leu specifically restored BLG synthesis from pre‐existing mRNA whereas AA also restored total protein synthesis. This restoration was associated with a more pronounced effect on 4E‐BP1 and S6K1 phosphorylation in bovine versus murine cells. Rapamycin specifically reduced Leu‐ and AA‐stimulated BLG translation initiation in a dose‐dependent manner. A further reduction was observed for Leu‐treated cells in the presence of LY294002, a PI3K (phosphatidylinositol 3‐kinase) inhibitor, which also reduced total protein synthesis. These findings suggest that direct signaling from AA to the translational machinery is involved in determining the rates of milk protein synthesis in mammary epithelial cells. J. Cell. Biochem. 98: 685–700, 2006. © 2006 Wiley‐Liss, Inc.
Mineralocorticoid receptor antagonists for heart failure

Introduction: Although mineralocorticoid receptor (MR) antagonists are indicated in systolic heart failure, they are underprescribed in patients with appropriate indications for their prescription and often used in those in whom the evidence for probable benefit is scant. The rate of adverse events in practice has exceeded that foreshadowed by randomized controlled trials (RCTs). With the recent publication of the landmark therapeutic trial (EMPHASIS), it is timely to review the appropriate use of these agents in heart failure. Areas covered: This review addresses the pathophysiological importance of MR activation in heart failure and summarizes pivotal RCTs of MR antagonists in heart failure. Expert opinion: MR antagonism reduces mortality and morbidity in heart failure with reduced systolic function in severe chronic disease, in heart failure complicating myocardial infarction and also in those with impaired systolic function (but only mild symptoms). Evidence for benefits in a significant proportion of ‘real-life’ patients with heart failure, including those with preserved left ventricular ejection fraction, is lacking. MR antagonism is an important part of the pharmaceutical armamentarium in managing heart failure but must be prescribed with careful case selection, taking note of the evidence of where risks are acceptable and benefits are likely.
Multicenter study investigating the postoperative progression of ossification of the posterior longitudinal ligament in the cervical spine: a new computer-assisted measurement.

OBJECT Ossification of the posterior longitudinal ligament (OPLL) often progresses after surgery, and this may cause late-onset neurological deterioration. There have been few studies, however, to clarify any correlation between progression and clinical outcome, partly because of the lack of studies involving reliable and reproducible methods by which detection of progression is made possible. The authors conducted a multicenter study to investigate the occurrence of postoperative progression and to elucidate the possible risk factors in a large-scale patient population, and a novel computer-assisted measurement method was used to provide the basis for future clinical studies. METHODS The authors analyzed lateral plain radiographs obtained immediately and at 1 and 2 years after surgery in 131 patients who underwent posterior decompression at 13 institutions. The x-ray films were transformed via scanner into digital images; the length and thickness of ossifications were measured using a new computer-assisted measurement system, and the incidence of progression was determined. Odds ratios for progression according to age group and types of OPLL were determined and compared to elucidate significant risk factors of progression. CONCLUSIONS This is the first multicenter study to investigate the incidence of OPLL progression after posterior decompression by using a standardized measurement method. The rate of postoperative progression at 2 years was 56.5%, which was comparable with results reported in other studies. Progression occurred more frequently in younger-age rather than in older-age patient populations at both 1 and 2 years postoperatively. Mixed-type and continuous-type OPLL progressed more frequently than the segmental-type lesion at 2 years. The results of the present study could serve as basis for future studies to assess the efficacy of drug therapy to prevent OPLL progression.
Pulmonary infection, and not systemic inflammation, accounts for increased concentrations of exhaled nitric oxide in patients with septic shock

Nitric oxide (NO) is a key mediator in the pathophysiology of septic shock that can be measured in exhaled breath. To assess whether a pulmonary infection itself or systemic inflammation is responsible for NO production, we determined exhaled NO in ventilated patients with respiratory and non-respiratory septic shock and compared it with the concentration in ventilated intensive care patients without systemic inflammation. In addition, the change of NO production over time and correlations with haemodynamic instability were evaluated. The controls without systemic inflammation, as witnessed by the absence of systemic inflammatory response syndrome criteria and low levels of interleukin-6, had similar concentrations of NO as the patients with non-respiratory septic shock. The respiratory sepsis patients exhaled more NO than the non-respiratory sepsis patients (p = 0.05), and a time dependent decline in time in both groups (p = 0.04). Exhaled NO did not correlate with markers of disease severity, systemic inflammation and haemodynamic instability. These data indicate that the infected lungs are the source of exhaled NO.