Second Data Release from the European Pulsar Timing Array: Challenging the Ultralight Dark Matter Paradigm.

Pulsar Timing Array experiments probe the presence of possible scalar or pseudoscalar ultralight dark matter particles through decade-long timing of an ensemble of galactic millisecond radio pulsars. With the second data release of the European Pulsar Timing Array, we focus on the most robust scenario, in which dark matter interacts only gravitationally with ordinary baryonic matter. Our results show that ultralight particles with masses 10^{-24.0} eV≲m≲10^{-23.3} eV cannot constitute 100% of the measured local dark matter density, but can have at most local density ρ≲0.3 GeV/cm^{3}.

Unresolved Gamma-Ray Sky through its Angular Power Spectrum.

The gamma-ray sky has been observed with unprecedented accuracy in the last decade by the Fermi -large area telescope (LAT), allowing us to resolve and understand the high-energy Universe. The nature of the remaining unresolved emission [unresolved gamma-ray background (UGRB)] below the LAT source detection threshold can be uncovered by characterizing the amplitude and angular scale of the UGRB fluctuation field. This Letter presents a measurement of the UGRB autocorrelation angular power spectrum based on eight years of Fermi-LAT Pass 8 data products. The analysis is designed to be robust against contamination from resolved sources and noise systematics. The sensitivity to subthreshold sources is greatly enhanced with respect to previous measurements. We find evidence (with ∼3.7σ significance) that the scenario in which two classes of sources contribute to the UGRB signal is favored over a single class. A double power law with exponential cutoff can explain the anisotropy energy spectrum well, with photon indices of the two populations being 2.55±0.23 and 1.86±0.15.

The genetic basis for susceptibility to Rift Valley fever disease in MBT/Pas mice.

The large variation in individual response to infection with Rift Valley fever virus (RVFV) suggests that host genetic determinants play a role in determining virus-induced disease outcomes. These genetic factors are still unknown. The systemic inoculation of mice with RVFV reproduces major pathological features of severe human disease, notably the hepatitis and encephalitis. A genome scan performed on 546 (BALB/c × MBT) F2 progeny identified three quantitative trait loci (QTLs), denoted Rvfs-1 to Rvfs-3, that were associated with disease susceptibility in MBT/Pas mice. Non-parametric interval-mapping revealed one significant and two suggestive linkages with survival time on chromosomes 2 (Rvfs-1), 5 (Rvfs-3) and 11 (Rvfs-2) with respective logarithm of odds (LOD) scores of 4.58, 2.95 and 2.99. The two-part model, combining survival time and survival/death, identified one significant linkage to Rvfs-2 and one suggestive linkage to Rvfs-1 with respective LOD scores of 5.12 and 4.55. Under a multiple model, with additive effects and sex as a covariate, the three QTLs explained 8.3% of the phenotypic variance. Sex had the strongest influence on susceptibility. The contribution of Rvfs-1, Rvfs-2 and Rvfs-3 to survival time of RVFV-infected mice was further confirmed in congenic mice.

Limits on Anisotropy in the Nanohertz Stochastic Gravitational Wave Background.

The paucity of observed supermassive black hole binaries (SMBHBs) may imply that the gravitational wave background (GWB) from this population is anisotropic, rendering existing analyses suboptimal. We present the first constraints on the angular distribution of a nanohertz stochastic GWB from circular, inspiral-driven SMBHBs using the 2015 European Pulsar Timing Array data. Our analysis of the GWB in the ~2-90 nHz band shows consistency with isotropy, with the strain amplitude in l>0 spherical harmonic multipoles ≲40% of the monopole value. We expect that these more general techniques will become standard tools to probe the angular distribution of source populations.

True perylene epitaxy on Ag(110) driven by site recognition effect.

We present a STM study of room temperature perylene adsorption on the Ag(110) surface. We have found a 2D perylene crystalline phase coexisting with the perylene liquid phase under thermal equilibrium. The reversible precipitation of the liquid phase at sub-monolayer coverage reveals the well ordered chiral crystalline phase existing in two enantiomorphic configurations of the ((-2)(3) (5)(2)) and ((2)(3) (5)(-2)) symmetry. This chiral phase is spatially separated into the 2D enantiopure islands of tens of nanometers size randomly distributed on the substrate and surrounded by the liquid medium. Analysis of surface registry of the crystalline phase combined with modeling of the intermolecular interactions indicates that its structure and symmetry is determined by a specific balance between the intermolecular attraction and intrinsic ability of the perylene aromatic board to recognize adsorption sites. The recognition effect was found to be strong enough to pin half of the perylene molecules into defined adsorption sites providing the structure skeleton. The attractive intermolecular interaction was found to be strong enough to bind another half of the molecules to the perylene skeleton shaping the true epitaxial structure.

Neutron star mass estimates from gamma-ray eclipses in spider millisecond pulsar binaries.

Reliable neutron star mass measurements are key to determining the equation of state of cold nuclear matter, but such measurements are rare. Black widows and redbacks are compact binaries consisting of millisecond pulsars and semi-degenerate companion stars. Spectroscopy of the optically bright companions can determine their radial velocities, providing inclination-dependent pulsar mass estimates. Although inclinations can be inferred from subtle features in optical light curves, such estimates may be systematically biased due to incomplete heating models and poorly understood variability. Using data from the Fermi Large Area Telescope, we have searched for gamma-ray eclipses from 49 spider systems, discovering significant eclipses in 7 systems, including the prototypical black widow PSR B1957+20. Gamma-ray eclipses require direct occultation of the pulsar by the companion, and so the detection, or significant exclusion, of a gamma-ray eclipse strictly limits the binary inclination angle, providing new robust, model-independent pulsar mass constraints. For PSR B1957+20, the eclipse implies a much lighter pulsar (1.81 ± 0.07 solar masses) than inferred from optical light curve modelling.

HIV genetic variation is directed and restricted by DNA precursor availability.

The effects of deoxynucleoside triphosphate (dNTP) imbalances on the fidelity of human immunodeficiency virus type 1 (HIV-1) replication were investigated. Using detergent permeabilized virions and biased dNTP concentrations different types of hypermutants were readily produced. However, the mutant spectrum was different from naturally occurring hypermutants demonstrating that the host cell may restrict variation. Using a genetic screen based on the blue/white beta-galactosidase complementation assay, G --> A hypermutants were recovered from HIV-infected thymidine treated U937 cells. Furthermore, hypermutants were recovered from 1 to 2% of resting or activated peripheral blood mononuclear cells indicating that small proportions of primary cells had distorted intracellular [dTTP] and [dCTP]. Such imbalances may underlie a proportion of somatic and germline point mutations and shape to some extent the evolution of mammalian and viral genomes.

A randomized, placebo-controlled, blind anti-AIDS clinical trial: safety and immunogenicity of a specific anti-IFN alpha immunization.

HIV-induced cytokine dysregulation, including overproduction of the antiproliferative and cytolytic IFN alpha cytokine, represents a major component of the immune disorders characterizing AIDS. To block the overproduction of IFN alpha we designed an AIDS vaccine combination which included both an anti-HIV and/or an anti-IFN alpha immunization. The safety and immunogenicity of this multicomponent vaccine were tested in mice, Cercopithecus, two HIV noninfected individuals, and six HIV-1 seropositive immunocompromised patients enrolled in a 1-year open clinical trial. We now report the result of a 9-month short-term randomized, blind, placebo-controlled clinical trial (Phase I/II) performed in HIV-1 patients (22 individuals) to confirm safety/tolerance of the anti-IFN alpha vaccine and its immunogenicity and to evaluate whether the complex vaccine initially used could be simplified by removal of HIV component(s). Three groups of patients received inactivated IFN alpha (i-IFN alpha) associated with the immunomodulator P40 with HIV-1 antigens (groups B and C) or without (group A), and one group (D) was placebo. The clinical follow-up documented among those receiving i-IFN-alpha showed that none developed AIDS and/or required antiretroviral chemotherapy. Viral load did not increase and CD4 cell count as well as cell-mediated immunity (CMI) stabilized or even significantly increased in group A. Immunogenicity of the preparations was determined by a positive delayed-type hypersensitivity (DTH) reaction to i-IFN alpha and the presence of serum antibodies to i-IFN alpha and to HIV-1 peptides, occurring only in treated patients. As previously planned, based on these safety data, the trial has been extended for an additional year and all patients were switched to protocol A (i-IFN alpha+P40). This second period of the trial, now open and ongoing, should allow us to evaluate further the innocuity of the i-IFN alpha preparation and whether anti-IFN alpha vaccine could provide a long-lasting CD4 cell count as well as CMI stabilization.

[Malignant tumoral lymphoma of the heart in human immunodeficiency virus infection: diagnosis by echocardiography]. / Lymphome malin tumoral de localisation cardiaque dans l'infection à virus de l'immunodéficience humaine; diagnostic par échocardiographie.

Non-Hodgkin's lymphoma is common in patients with human immuno-deficiency virus infection, but an intracardiac localisation is rare. In this case, the malignant lymphoma presented with a degradation of the patient's condition and signs of right-sided cardiac failure. Echocardiography showed a polylobed mass invading the right ventricle. Computerised tomography provided detailed information of the extension of the lymphoma in the different cardiac chambers. The patient died after a few days of a low cardiac output state. The malignant nature of the tumour was confirmed at biopsy. This case of cardiac lymphoma in a patient with immunodepression confirms the fatal character of this condition in the very short term after the appearance of the first clinical signs, the value of echocardiography in the diagnosis and the difficulty in implementing any effective therapeutic measure.

[Percutaneous angioplasty of the infra-renal aorta. Report of 9 cases]. / Angioplastie endoluminale de l'aorte abdominale sous-rénale. A propos de 9 cas.

Between June 1996 and September 2000, nine angioplasties of the infra-renal aorta were performed in two Surgical Vascular Centers (Hospital Saint-Joseph, Paris, Polyclinic La Baule), in 6 men and three women age ranged from 36 to 72 years (middle age 48 years and 2 months). Eight of these patients presented important stenoses of the middle infra-renal aorta, or in the aortic bifurcation, one of them presented an occlusion, leading to severe intermittent claudication, and rest pain. After endoluminal kissing balloon angioplasty, five aortic stents (five patients), and six iliac primitive arteries stents (in three patients), extended beyond the aorta, were placed. One isolated angioplasty was also performed. All the procedures were performed in the operative room, with good results, except for one patient requiring emergency aorto-bi-femoral by-pass, because of acute leg ischemia, immediately following the procedure. Follow-up was clinical, with Us-Doppler scan, and angiogram in all cases. After 36 months follow-up (4-52), all patients are asymptomatic, with permeable stents. This technique is well-known since 1980, without excessive morbidity. Aortic angioplasty represents the right technique, with good long-term results, for middle or terminal aorta atheromatous stenosis, according to classical aorto-bi-femoral by-passes. Final result depends on associated iliac arteries stenoses.

[X-ray computed tomographic diagnosis of primary cardiac malignant lymphoma in AIDS]. / Diagnostic tomodensitométrique d'un lymphome malin cardiaque primitif au cours du SIDA.

Primary lymphomas rarely affect the heart. The myocardial disease is usually latent and the diagnosis is based on post mortem observations. The cardiac symptoms do not reveal the disease and symptomatology is not specific. Our observation shows the complementarity of non invasive techniques, for a better screening of cardiac tumoral forms. Although echocardiography is the main examination, CT scan provides a detection of infiltrative forms and of extracardiac extension. Concurrently, MRI remains the method of choice to display beginning infiltrative forms, revealed by pericardial effusion in AIDS disease.

[Shock occurring shortly after inferior vena cava interruption using an endovascular device: think of filter thrombosis]. / Choc survenant précocement après la pose d'un filtre endovasculaire pour interruption de la veine cave inférieure : penser à la thrombose.

We report the case of a 47-year-old man who experienced a pulmonary embolism associated with a femoral thrombus after a traumatic intracranial haematoma and had caval interruption using a new generation endovascular percutaneous filter. A shock occurred soon after the procedure, associated with inferior cava system inflation related to a filter thrombosis. This is a rare complication since the cessation of surgical cava interruptions. The situation became stable after intensive volume expansion. This report underlines the risk of complication associated to vena cava interruption despite the use of new generation filters and the significance of mechanical measures in prevention of thrombosis when anticoagulants are contraindicated.

Binary millisecond pulsar discovery via gamma-ray pulsations.

Millisecond pulsars, old neutron stars spun up by accreting matter from a companion star, can reach high rotation rates of hundreds of revolutions per second. Until now, all such "recycled" rotation-powered pulsars have been detected by their spin-modulated radio emission. In a computing-intensive blind search of gamma-ray data from the Fermi Large Area Telescope (with partial constraints from optical data), we detected a 2.5-millisecond pulsar, PSR J1311-3430. This unambiguously explains a formerly unidentified gamma-ray source that had been a decade-long enigma, confirming previous conjectures. The pulsar is in a circular orbit with an orbital period of only 93 minutes, the shortest of any spin-powered pulsar binary ever found.

Angiotensin II-induced transcriptional activation of the cyclin D1 gene is mediated by Egr-1 in CHO-AT(1A) cells.

Cyclin D1 protein expression is regulated by mitogenic stimuli and is a critical component in the regulation of G(1) to S phase progression of the cell cycle. Angiotensin II (Ang II) binds to specific G protein-coupled receptors and is mitogenic in Chinese hamster ovary cells stably expressing the rat vascular Ang II type 1A receptor (CHO-AT(1A)). We recently reported that in these cells, Ang II induced cyclin D1 promoter activation and protein expression in a phosphatidylinositol 3-kinase (PI3K)-, SHP-2-, and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)-dependent manner (Guillemot, L., Levy, A., Zhao, Z. J., Béréziat, G., and Rothhut, B. (2000) J. Biol. Chem. 275, 26349-26358). In this report, transfection studies using a series of deleted cyclin D1 promoters revealed that two regions between base pairs (bp) -136 and -96 and between bp -29 and +139 of the human cyclin D1 promoter contained regulatory elements required for Ang II-mediated induction. Mutational analysis in the -136 to -96 bp region provided evidence that a Sp1/early growth response protein (Egr) motif was responsible for cyclin D1 promoter activation by Ang II. Gel shift and supershift studies showed that Ang II-induced Egr-1 binding involved de novo protein synthesis and correlated well with Egr-1 promoter activation. Both U0126 (an inhibitor of the MAPK/ERK kinase MEK) and wortmannin (an inhibitor of PI3K) abrogated Egr-1 endogenous expression and Egr-1 promoter activity induced by Ang II. Moreover, using a co-transfection approach, we found that Ang II induction of Egr-1 promoter activity was blocked by dominant-negative p21(ras), Raf-1, and tyrosine phosphatase SHP-2 mutants. Identical effects were obtained when inhibitors and dominant negative mutants were tested on the -29 to +139 bp region of the cyclin D1 promoter. Taken together, these findings demonstrate that Ang II-induced cyclin D1 up-regulation is mediated by the activation and specific interaction of Egr-1 with the -136 to -96 bp region of the cyclin D1 promoter and by activation of the -29 to +139 bp region, both in a p21(ras)/Raf-1/MEK/ERK-dependent manner, and also involves PI3K and SHP-2.

Surface miller index dependence of Auger neutralization of ions on surfaces.

Neutralization of He+ ions in grazing incidence scattering on Ag(111) and Ag(110) surfaces is studied. These measurements reveal the existence of an order of magnitude difference in the probability of ion survival on Ag(110) and Ag(111). The experimental results are discussed in terms of survival from Auger neutralization, whose rates are derived theoretically. Molecular dynamics simulation of scattered ion trajectories is performed and the surviving ion fractions are then calculated using the theoretical Auger neutralization rates, without adjustable parameters. The calculations agree quite well with the experimental data and show that the observed differences in the neutralization probabilities on these surfaces are related to different extensions of the electron density beyond the surface, resulting from different atomic packing.

The protein-tyrosine phosphatase SHP-2 is required during angiotensin II-mediated activation of cyclin D1 promoter in CHO-AT1A cells.

Angiotensin II (Ang II) binds to specific G protein-coupled receptors and is mitogenic in Chinese hamster ovary (CHO) cells stably expressing a rat vascular angiotensin II type 1A receptor (CHO-AT(1A)). Cyclin D1 protein expression is regulated by mitogens, and its assembly with the cyclin-dependent kinases induces phosphorylation of the retinoblastoma protein pRb, a critical step in G(1) to S phase cell cycle progression contributing to the proliferative responses. In the present study, we found that in CHO-AT(1A) cells, Ang II induced a rapid and reversible tyrosine phosphorylation of various intracellular proteins including the protein-tyrosine phosphatase SHP-2. Ang II also induced cyclin D1 protein expression in a phosphatidylinositol 3-kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)-dependent manner. Using a pharmacological and a co-transfection approach, we found that p21(ras), Raf-1, phosphatidylinositol 3-kinase and also the catalytic activity of SHP-2 and its Src homology 2 domains are required for cyclin D1 promoter/reporter gene activation by Ang II through the regulation of MAPK/ERK activity. Our findings suggest for the first time that SHP-2 could play an important role in the regulation of a gene involved in the control of cell cycle progression resulting from stimulation of a G protein-coupled receptor independently of epidermal growth factor receptor transactivation.

Constrained evolution of human immunodeficiency virus type 1 protease during sequential therapy with two distinct protease inhibitors.

Human immunodeficiency virus type 1 (HIV-1) variants that have developed protease (PR) inhibitor resistance most often display cross-resistance to several molecules within this class of antiretroviral agents. The clinical benefit of the switch to a second PR inhibitor in the presence of such resistant viruses may be questionable. We have examined the evolution of HIV-1 PR genotypes and phenotypes in individuals having failed sequential treatment with two distinct PR inhibitors: saquinavir (SQV) followed by indinavir (IDV). In viruses where typical SQV resistance mutations were detected before the change to IDV, the corresponding mutations were maintained under IDV, while few additional mutations emerged. In viruses where no SQV resistance mutations were detected before the switch to IDV, typical SQV resistance profiles emerged following the introduction of IDV. We conclude that following suboptimal exposure to a first PR inhibitor, the introduction of a second molecule of this class can lead to rapid selection of cross-resistant virus variants that may not be detectable by current genotyping methods at the time of the inhibitor switch. Viruses committed to resistance to the first inhibitor appear to bear the "imprint" of this initial selection and can further adapt to the selective pressure exerted by the second inhibitor following a pathway that preserves most of the initially selected mutations.

Predominance of CCR5-dependent HIV-1 subtype E isolates in Cambodia.

To investigate the genetic and biologic features of HIV-1 strains circulating in Cambodia, viruses from 95 HIV-1-seropositive individuals were subtyped by heteroduplex mobility assay (HMA) and 23 were further analyzed for their biologic characteristics. Eighty-nine individuals were clearly infected by HIV-1 subtype E. The other six samples were sequenced, together with 17 HMA subtype E samples. All but one of the 23 Cambodian env sequences clustered with previously described Thai and Vietnamese subtype E sequences, bearing a GPGQ motif at the tip of the V3 loop; the last had a GPGR motif and was phylogenetically equidistant from Asian and African subtype E viruses. Nonsyncytium-inducing, CCR5-dependent viruses predominated in patients of clinical stage B even in some with a high viral load and were detected in about 50% of the patients of stage C. All syncytium-inducing strains, mostly from AIDS patients, used both CCR5 and CXCR4. The presence of syncytium-inducing viruses did not correlate with the plasma viral load. These data show that CCR5-dependent HIV-1 subtype E is currently predominant in Cambodia. The analysis of clinical and virologic markers strongly supports the idea that dynamics of the viral population during subtype E infection in Southeast Asia is similar to that of subtype B infection in Europe and the United States.

PIP: The National AIDS Control and Prevention Program of the Cambodian ministry of health has reported that the prevalence of HIV-1 infection among blood donors in Cambodia increased from less than 1% in 1991 to 4% in 1996, and that 39.3% of prostitutes, 7.1% of military personnel, 3.2% of pregnant women, and 5.2% of tuberculosis patients were infected in 1997. Findings are presented from an investigation of the genetic and biological features of HIV-1 strains in Cambodia. Viruses from 95 HIV-1-seropositive individuals were subtyped by heteroduplex mobility assay (HMA) and 23 were further analyzed for their biologic characteristics. 89 people were clearly infected with HIV-1 subtype E. The other 6 samples, however, were sequenced together with 17 HMA subtype E samples. All but 1 of these latter 23 Cambodian env sequences clustered with previously described Thai and Vietnamese subtype E sequences bearing a GPGQ motif at the tip of the V3 loop, with the last having a GPGR motif and being phylogenetically equidistant from Asian and African subtype E viruses. Nonsyncytium-inducing, CCR5-dependent viruses predominated in patients of clinical stage B, and were detected in about half of the stage C patients. All syncytium-inducing strains, mostly from AIDS patients, used both CCR5 and CXCR4. The presence of syncytium-inducing viruses did not correlate with the plasma viral load. These data show that CCR5-dependent HIV-1 subtype E currently predominates in Cambodia. The dynamics of the viral population during subtype E infection in Southeast Asia appear to be similar to that of subtype B infection in Europe and the US.