Core-binding factor leukemia hijacks the T-cell-prone PU.1 antisense promoter.

The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of crucial transcription factors. One of the key master regulators in the hematopoietic systems is PU.1. Reduced levels of PU.1 are characteristic for human acute myeloid leukemia (AML) and are known to induce AML in mouse models. Here, we show that transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core-binding factor (CBF) fusions RUNX1-ETO and CBFß-MYH11 in t(8;21) and inv(16) AML, respectively, activate the PU.1 antisense promoter that results in a shift from sense toward antisense transcription and myeloid differentiation blockade. In patients with CBF-AML, we found that an elevated antisense/sense transcript and promoter accessibility ratio represents a hallmark compared with normal karyotype AML or healthy CD34+ cells. Competitive interaction of an enhancer with the proximal or the antisense promoter forms a binary on/off switch for either myeloid or T-cell development. Leukemic CBF fusions thus use a physiological mechanism used by T cells to decrease sense transcription. Our study is the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. Hence, this disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.

Splitting Probabilities of Symmetric Jump Processes.

We derive a universal, exact asymptotic form of the splitting probability for symmetric continuous jump processes, which quantifies the probability π_{0,[under x]_}(x_{0}) that the process crosses x before 0 starting from a given position x_{0}∈[0,x] in the regime x_{0}≪x. This analysis provides in particular a fully explicit determination of the transmission probability (x_{0}=0), in striking contrast with the trivial prediction π_{0,[under x]_}(0)=0 obtained by taking the continuous limit of the process, which reveals the importance of the microscopic properties of the dynamics. These results are illustrated with paradigmatic models of jump processes with applications to light scattering in heterogeneous media in realistic 3D slab geometries. In this context, our explicit predictions of the transmission probability, which can be directly measured experimentally, provide a quantitative characterization of the effective random process describing light scattering in the medium.

Muography of different structures using muon scattering and absorption algorithms.

In recent decades, muon imaging has found a plethora of applications in many fields. This technique succeeds to infer the density distribution of big inaccessible structures where conventional techniques cannot be used. The requirements of different applications demand specific implementations of image reconstruction algorithms for either multiple scattering or absorption-transmission data analysis, as well as noise-suppression filters and muon momentum estimators. This paper presents successful results of image reconstruction techniques applied to simulated data of some representative applications. In addition to well-known reconstruction methods, a novel approach, the so-called µCT, is proposed for the inspection of spent nuclear fuel canisters. Results obtained based on both µCT and the maximum-likelihood expectation maximization reconstruction algorithms are presented.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.

INFN muon tomography demonstrator: past and recent results with an eye to near-future activities.

A short description of the muon tomography demonstrator at the INFN Laboratori Nazionali di Legnaro near Padua, Italy, is given and the principal achievements owing to the data collected at that experimental facility are presented. In particular, the feasibility studies for several applications based on the muon-tomographic technology, within national and European projects, are discussed. The experimental problems and the procedures used to improve the performance are underlined. In addition, new activities and the related detector optimization are illustrated.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.

Muon-Induced Neutrons Do Not Explain the DAMA Data.

We present an accurate model of the muon-induced background in the DAMA/LIBRA experiment. Our work challenges proposed mechanisms which seek to explain the observed DAMA signal modulation with muon-induced backgrounds. Muon generation and transport are performed using the MUSIC/MUSUN code, and subsequent interactions in the vicinity of the DAMA detector cavern are simulated with Geant4. We estimate the total muon-induced neutron flux in the detector cavern to be Φ(n)(ν)=1.0 × 10(-9) cm(-2) s(-1). We predict 3.49 × 10(-5) counts/day/kg/keV, which accounts for less than 0.3% of the DAMA signal modulation amplitude.

Ultra-narrow linewidth, stable and tunable laser source for optical communication systems and spectroscopy.

A novel ultra-narrow linewidth, stable and tunable single-line laser source is demonstrated and experimentally performed. The single spectral line laser is achieved by selecting and amplifying one spectral comb line of a femtosecond-fiber laser via polarization pulling assisted stimulated Brillouin scattering. Stabilization and tuning is performed by additional modulation. First proof of concept results show possible linewidths below 1 Hz and an SNR of 47 dB with a tunability of more than 100 nm and a relative stability of ±160 mHz over 5 h. Such a laser source gives high potential for many different applications like spectroscopy and optical communications.

Extreme value statistics of jump processes.

We investigate extreme value statistics (EVS) of general discrete time and continuous space symmetric jump processes. We first show that for unbounded jump processes, the semi-infinite propagator G_{0}(x,n), defined as the probability for a particle issued from zero to be at position x after n steps whilst staying positive, is the key ingredient needed to derive a variety of joint distributions of extremes and times at which they are reached. Along with exact expressions, we extract universal asymptotic behaviors of such quantities. For bounded, semi-infinite jump processes killed upon first crossing of zero, we introduce the strip probability µ_{0,[under x]̲}(n), defined as the probability that a particle issued from zero remains positive and reaches its maximum x on its nth^{} step exactly. We show that µ_{0,[under x]̲}(n) is the essential building block to address EVS of semi-infinite jump processes, and obtain exact expressions and universal asymptotic behaviors of various joint distributions.

Leftward, rightward, and complete exit-time distributions of jump processes.

First-passage properties of continuous stochastic processes confined in a one-dimensional interval are well described. However, for jump processes (discrete random walks), the characterization of the corresponding observables remains elusive, despite their relevance in various contexts. Here we derive exact asymptotic expressions for the leftward, rightward, and complete exit-time distributions from the interval [0,x] for symmetric jump processes starting from x_{0}=0, in the large x and large time limit. We show that both the leftward probability F_{[under 0]̲,x}(n) to exit through 0 at step n and rightward probability F_{0,[under x]̲}(n) to exit through x at step n exhibit a universal behavior dictated by the large-distance decay of the jump distribution parametrized by the Levy exponent µ. In particular, we exhaustively describe the n≪(x/a_{µ})^{µ} and n≫(x/a_{µ})^{µ} limits and obtain explicit results in both regimes. Our results finally provide exact asymptotics for exit-time distributions of jump processes in regimes where continuous limits do not apply.

Joint statistics of space and time exploration of one-dimensional random walks.

The statistics of first-passage times of random walks to target sites has proved to play a key role in determining the kinetics of space exploration in various contexts. In parallel, the number of distinct sites visited by a random walker and related observables has been introduced to characterize the geometry of space exploration. Here, we address the question of the joint distribution of the first-passage time to a target and the number of distinct sites visited when the target is reached, which fully quantifies the coupling between the kinetics and geometry of search trajectories. Focusing on one-dimensional systems, we present a general method and derive explicit expressions of this joint distribution for several representative examples of Markovian search processes. In addition, we obtain a general scaling form, which holds also for non-Markovian processes and captures the general dependence of the joint distribution on its space and time variables. We argue that the joint distribution has important applications to various problems, such as a conditional form of the Rosenstock trapping model, and the persistence properties of self-interacting random walks.

Distribution of the span of one-dimensional confined random processes before hitting a target.

We derive the distribution of the number of distinct sites visited by a random walker before hitting a target site of a finite one-dimensional (1D) domain. Our approach holds for the general class of Markovian processes with connected span-i.e., whose trajectories have no "holes." We show that the distribution can be simply expressed in terms of splitting probabilities only. We provide explicit results for classical examples of random processes with relevance to target search problems, such as simple symmetric random walks, biased random walks, persistent random walks, and resetting random walks. As a by-product, explicit expressions for the splitting probabilities of all these processes are given. Extensions to reflecting boundary conditions, continuous processes, and an example of a random process with a nonconnected span are discussed.

Influence of a phase transition of ice on the heat and mass balance of comets.

Differences in gas production rates of comets may be explained in part by the phase transition of ice in the comet nuclei.

Proteinases of Pseudomonas aeruginosa evoke mucin release by tracheal epithelium.

We have determined the potential of exoproducts from pathogenic bacteria to stimulate the release of high molecular weight mucins from goblet cells of airway epithelium in a rabbit tracheal explant system. Culture supernatants from proteolytic strains of Pseudomonas aeruginosa and Serratia marcescens, but not supernatants from a number of non-proteolytic strains, released mucins from goblet cells. Highly purified elastase and alkaline proteinase from P. aeruginosa stimulated goblet cell mucin release in a dose-dependent fashion. Lipopolysaccharide, exotoxin A, and alginate of P. aeruginosa did not possess mucin release properties. Proteolytic activity was required for mucin release by P. aeruginosa elastase, but such release in goblet cells was not mediated by cyclic AMP. Morphologic studies suggested rapid release of mucins from goblet cells was response to elastase by a process resembling apocrine secretion. Several nonbacterial proteinases mimicked the effect of Pseudomonas proteases. These studies provide support for the hypothesis that bacterial and other play a role in the pathogenesis of mucus hypersecretion in acute and chronic lung infections.

Isotopic constraints on water source mixing, network leakage and contamination in an urban groundwater system.

Water supply in developing countries is prone to large water losses due to leaky distribution networks and defective sewers, which may affect groundwater quality and quantity in urban areas and result in complex subsurface mixing dynamics. In this study, a multi-stable isotope approach was used to investigate spatiotemporal fluctuations of surface and sub-surface water source partitioning and mixing, and to assess nitrogen (N) contamination in the urban water cycle of As-Salt, Jordan. Water import from the King Abdullah Canal (KAC), mains waters from the network, and wastewater are characterized by distinct isotopic signatures, which allowed us to quantify city effluents into the groundwater. Temporal variations in isotopic signatures of polluted groundwater are explained by seasonally fluctuating inflow, and dilution by water that originates from Lake Tiberias and enters the urban water cycle via the KAC. Isotopic analysis (N and O) and comparison between groundwater nitrate and nitrate from mains water, water imports and wastewater confirmed that septic waste from leaky sewers is the main contributor of nitrate contamination. The nitrate of strongly contaminated groundwater was characterized by highest δ15NNO3 values (13.3±1.8‰), whereas lowest δ15NNO3 values were measured in unpolluted groundwater (6.9‰). Analogously, nitrate concentration and isotopic ratios were used for source partitioning and qualitatively confirmed δDH2O and δ18OH2O-based estimates. Dual water isotope endmember mixing calculations suggest that city effluents from leaky networks and sewers contribute 30-64% to the heavily polluted groundwater. Ternary mixing calculations including also chloride revealed that 5-18% of the polluted groundwater is wastewater. Up to two thirds of the groundwater originates from mains, indicating excessive water loss from the network, and calling for improved water supply management.

Echocardiographic Pulmonary Hypertension Predicts Post-transplantation Renal Allograft Failure.

BACKGROUND: Pulmonary hypertension in the setting of renal transplantation has been associated with early allograft dysfunction and increased mortality, but this relationship has not been extensively studied. METHODS: We performed a retrospective cohort study of adult patients who underwent their first renal transplantation in the years 2003-2009 and had pre-transplantation echocardiograms. Pulmonary hypertension was defined as right ventricular systolic pressure ≥40 mm Hg in the absence of left-sided valvular disease and/or left ventricular ejection fraction ≤50%. Eighty-two of 205 patients (40%) met the inclusion criteria. The relationship between pulmonary hypertension and death-censored allograft failure (hemodialysis dependence or retransplantation) and serum creatinine was assessed with the use of Cox hazard regression and generalized mixed models. RESULTS: The presence of pulmonary hypertension was associated with a 3-fold increase in the risk of death-censored allograft failure (95% confidence interval, 1.20-7.32; P = .02). Failure rates were 19% at 24 months and 51% at 96 months for those with pulmonary hypertension versus 7% at 24 months and 20% at 86 months for those without pulmonary hypertension (P = .01). Among those without graft failure, there was an increase in creatinine levels after transplantation (P = .01). Effect estimates were unchanged by adjustment for multiple covariates and when pulmonary hypertension was defined as right ventricular systolic pressure ≥36 mm Hg. CONCLUSIONS: Pulmonary hypertension before renal transplantation carries a 3-fold increased risk of death-censored allograft failure. The relationship between the pulmonary circulation and renal allograft failure warrants further study.

Integrating groundwater into urban water management.

The management of urban groundwater resources is directly linked to urban water supply and drainage concepts. A proper integration of groundwater into urban water management plans is recommended for long-term planning. The paper describes the development of a new modelling suite which addresses the urban water and solute balance in a holistic way. Special focus has been placed on the assessment of the impact of sewer leakage on groundwater in four case study cities. Tools for the prediction of sewer leakage including the assessment of uncertainties are now available. Field investigations in four European case study cities were able to trace the influence of sewer leakage on urban groundwater using microbiological indicators and pharmaceutical residues.

Infection of baboons with a simian immunodeficiency virus/HIV-1 chimeric virus constructed with an HIV-1 Thai subtype E envelope.

OBJECTIVE: To construct an infectious chimeric simian immunodeficiency virus/HIV-1 (SHIV) with the envelope of a Thai subtype E HIV-1 strain for use in a non-human primate model. METHODS: A novel SHIV genome was derived using the sequences of the ectodomain of the envelope gene from the Thai subtype E strain, HIV-1(9466). This SHIV (SHIV9466.33) was recovered by cocultivation from human peripheral blood mononuclear cells (PBMC) after transfection of human rhabdosarcoma cells. Rhesus macaque and baboon PBMC were screened in vitro for susceptibility to infection with SHIV9466.33. After successful infection of baboon PBMC, four animals were inoculated intravenously with SHIV9466.33 and monitored for plasma viral RNA, virus isolation from the PBMC, seroconversion, T-cell subsets, and signs of disease. RESULTS: SHIV9466.33 was able to infect PBMC from 12 out of 14 baboons. All four of the baboons selected for in vivo inoculation became infected. Peak plasma viral RNA levels of 8000 to 700,000 RNA copies/ml were measured at 2 weeks post-inoculation. Virus was isolated from the PBMC of all four baboons during acute infection, and all seroconverted. Although transient declines in CD4+ T-cells were observed during early infection, CD4+ levels remained within normal ranges thereafter. In contrast, in vitro cultures of PBMC of four rhesus macaques were not susceptible to infection with SHIV9466.33. CONCLUSION: SHIV9466.33 containing an HIV-1 subtype E envelope displayed tropism for baboon PBMC but not for rhesus macaque PBMC. This chimeric virus established infection and induced antiviral antibodies in baboons inoculated by the intravenous route with cell-free virus. Thus, infection of baboons with SHIV9466.33 will serve as an important animal model for future studies of HIV-1 vaccine efficacy.

Ceftazidime therapy in patients with cystic fibrosis and multiply-drug-resistant pseudomonas.

The in vitro activity of ceftazidime against Pseudomonas aeruginosa and P. cepacia isolates from patients with cystic fibrosis was compared with that of other antipseudomonal drugs. Ceftazidime was as potent as imipenem against P. aeruginosa and the only drug effective against P. cepacia. An evaluation of the elimination kinetics of ceftazidime in 20 cystic fibrosis patients revealed an elimination half-life of 1.76 hours, an apparent distribution volume of 0.27 liters/kg, and a serum clearance rate of 133.9 ml/minute/1.73m2. Urinary recovery of ceftazidime was 87 percent within the first 24 hours after administration of the drug, with 65 percent recovered in the first two-hour fraction. Probenecid administration had no effect on the elimination kinetics of ceftazidime. Forty-three patients who had either shown no response to conventional therapy or had sputum Pseudomonas isolates that were susceptible only to ceftazidime received 75 courses of therapy. In 67 percent of these patients, the clinical response, when evaluated using an objective clinical efficacy scoring system, was considered favorable. Clinical failures were not associated with the development of drug resistance. Thus, ceftazidime can be recommended for the treatment of acute pulmonary exacerbations in patients with cystic fibrosis.

Inhibition of murine splenic T lymphocyte proliferation by 2-deoxy-D-glucose-induced metabolic stress.

Female Swiss-Webster mice were injected with the glucose analogue 2-deoxy-D-glucose (2-DG), which when administered to rodents induces acute periods of metabolic stress. A single or multiple injections of 2-DG invoked a stress response, as evidenced by increases in serum corticosterone levels. The influence of this metabolic stressor on the blastogenic potential of splenic T lymphocytes was then examined. It was found that one, two, or three injections of 2-DG resulted in depressed T cell proliferative responses, with an attenuation of the effect occurring by the fifth injection. The 2-DG-induced inhibition of T cell proliferation was not attributable to 2-DG-induced cytolysis, as in vitro incubation of naive T cells with varying concentrations of 2-DG did not result in a reduction in cell number or viability, and flow cytometric analysis demonstrated that percentages of CD3, CD4, and CD8 splenic T cells were not altered as a result of 2-DG-induced stress. Incubating naive T cells in varying concentrations of 2-DG resulted in a dose-dependent inhibition of T cell blastogenic potential. Following in vivo exposure to 2-DG, T cell proliferation did not return to normal levels until 3 days after the cessation of 2-DG injections. Administering the beta-adrenergic receptor antagonist propranolol did not reverse the inhibited lymphoproliferation in 2-DG-treated mice. The inhibition in T cell proliferation was not observed, however, in mice that had been adrenalectomized or hypophysectomized and injected with 2-DG.(ABSTRACT TRUNCATED AT 250 WORDS)

Right ventricular dysfunction in chronic obstructive pulmonary disease. Evaluation and management.

Cor pulmonale is an important consequence of COPD. Although the incidence is not precisely known, it is seen more frequently in patients with hypoxemia, CO2 retention and severely reduced FEV1. When present, it limits peripheral oxygen delivery, increases shortness of breath, and reduces exercise endurance. It is also associated with higher mortality rates independent of other prognostic variables. Numerous factors may contribute to the development of cor pulmonale in patients with COPD, but its primary cause is chronic alveolar hypoxia resulting in pulmonary vasoconstriction, vascular remodeling and pulmonary hypertension. The physical exam, chest radiograph and ECG may be helpful in detecting the presence of cor pulmonale, but because of anatomic changes that occur in the chest, these tests are often insensitive in patients with COPD. Noninvasive diagnostic techniques utilizing Doppler echocardiography and radionuclide angiography allow for detection of RV dysfunction at an earlier stage and in most cases, preclude the need for right heart catheterization. LTO2 is the only therapy shown to improve survival in patients with COPD. However, statistical proof correlating improvements in pulmonary hemodynamics with increased survival is lacking. Bronchodilators, such as the beta 2 agonists and especially theophylline, may have beneficial effects on pulmonary hemodynamics in addition to their effect on respiratory function and are useful in COPD when RV dysfunction is present. Diuretics and phlebotomy are also useful in improving symptoms in appropriate patients. Vasodilators such as calcium channel blockers and ACE-inhibitors may improve pulmonary hemodynamics acutely, but may lower arterial PO2 by worsening ventilation-perfusion matching or blunt the improvement in pulmonary hemodynamics seen with supplemental oxygen. The long-term benefits of these agents have not been proven and their routine use in patients with cor pulmonale due to COPD cannot be recommended.

Pulmonary complications from alveolar accumulation of carbonaceous material in a cocaine smoker.

A 27-year-old woman presented with cough, fever, and pulmonary infiltrates after heavy cocaine smoking. Large amounts of carbonaceous material and pigment-laden macrophages were recovered by bronchoalveolar lavage. Alveolar deposition of particulate matter from heavy cocaine smoking has not been previously reported and may have been the cause of this patient's symptoms and abnormal findings on chest radiograph.