Thanks to the success of current gamma-ray telescopes (Fermi, H.E.S.S., MAGIC, VERITAS), and in view of the prospects of planned observatories such as the Cherenkov Telescope Array (CTA) or the ...High-Altitude Water Cherenkov Observatory (HAWC), gamma-ray astronomy is becoming an integral part of modern astrophysical research. Analysis today relies on a large diversity of tools and software frameworks that were specifically and independently developed for each instrument. With the aim of unifying the analysis of gamma-ray data, we are currently developing GammaLib (http://sourceforge.net/projects/gammalib), a C++ library interfaced to Python that provides a framework for an instrument independent analysis of gamma-ray data. On top of GammaLib we have created ctools (http://cta.irap.omp.eu/ctools), a set of analysis executables that is being developed as one of the prototypes for the CTA high-level science analysis framework, but which is equally suited for the analysis of gamma-ray data from the existing Fermi-LAT telescope and current Cherenkov telescope arrays. In particular, ctools and GammaLib provide the novel opportunity of a simultaneous multi-instrument analysis. We present the status of the software development, and illustrate its capabilities with a spectral analysis of the Crab nebula emission over seven decades in energy (1 MeV to 10 TeV) using multi-instrument (COMPTEL, Fermi-LAT, H.E.S.S.) gamma-ray observations as well as a simulation of a CTA observation of the supernova remnant RX J1713.7-3946.
Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic
. The C5a complement factor and ...its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes
. Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a-C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a-C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19.
One important limitation of the widely used insect baculovirus overexpression system is its inefficiency to properly process heterologous proteins which are initially biosynthesized as larger ...inactive precursor proteins. One example is transforming growth factor beta 1 (TGF beta 1), a 25-kDa homodimeric protein with pleiotropic functions. As many growth factors, the inactive TGF beta 1 precursor molecule needs to be proteolytically cleaved C-terminal to a basic sequence to yield the mature and active homodimer. In insect cells, a large proportion of overexpressed TGF beta 1 was found in an inactive precursor form suggesting that the levels of endogenous convertases are limiting for the production of mature and bioactive TGF beta 1 in this system. We have demonstrated that furin, a member of a novel family of mammalian prohormone convertases (PCs) can efficiently process TGF beta 1 precursor resulting in the production of the mature and active growth factor. Taking advantage of this observation, we have developed an improved overproduction system for TGF beta 1 by coexpressing prohTGF beta 1 and human furin convertase in High Five cells. Using this system, the production of mature active TGF beta 1 increased in a dose-dependent fashion reaching up to 7.8-fold the amount obtained with the growth factor only. Thus, eliminating the rate-limiting step in recombinant TGF beta 1 production maximizes its processing efficiency and the yield of the mature active growth factor. Such simple and efficient technology could be useful for large scale production of other proproteins which undergo similar maturation processes and share furin recognition sequences at the junction between the proregion and the mature polypeptide.
We present the results of the analysis of 8 years of Fermi-LAT data of the pulsar/pulsar wind nebula complex PSR J0205+6449/3C 58. Using a contemporaneous ephemeris, we carried out a detailed ...analysis of PSR J0205+6449 both during its off-peak and on-peak phase intervals. 3C 58 is significantly detected during the off-peak phase interval. We show that the spectral energy distribution at high energies is the same disregarding the phases considered, and thus that this part of the spectrum is most likely dominated by the nebula radiation. We present results of theoretical models of the nebula and the magnetospheric emission that confirm this interpretation. Possible high-energy flares from 3C 58 were searched for, but none was unambiguously identified.
See Meschia (doi:10.1093/brain/awy066) for a scientific commentary on this article.
The vein of Galen aneurysmal malformation is one of the most frequent paediatric cerebral vascular malformations. ...Vivanti et al. show that heterozygous loss-of-function mutations of EPHB4 are responsible for this congenital anomaly. EPHB4 knockdown in zebrafish disrupts the embryonic precursor of the vein of Galen, implicating EPHB4 in cerebral vascular differentiation.
Abstract
See Meschia (doi:10.1093/brain/awy066) for a scientific commentary on this article.
Vein of Galen aneurysmal malformation is a congenital anomaly of the cerebral vasculature representing 30% of all paediatric vascular malformations. We conducted whole exome sequencing in 19 unrelated patients presenting this malformation and subsequently screened candidate genes in a cohort of 32 additional patients using either targeted exome or Sanger sequencing. In a cohort of 51 patients, we found five affected individuals with heterozygous mutations in EPHB4 including de novo frameshift (p.His191Alafs*32) or inherited deleterious splice or missense mutations predicted to be pathogenic by in silico tools. Knockdown of ephb4 in zebrafish embryos leads to specific anomalies of dorsal cranial vessels including the dorsal longitudinal vein, which is the orthologue of the median prosencephalic vein and the embryonic precursor of the vein of Galen. This model allowed us to investigate EPHB4 loss-of-function mutations in this disease by the ability to rescue the brain vascular defect in knockdown zebrafish co-injected with wild-type, but not truncated EPHB4, mimicking the p.His191Alafs mutation. Our data showed that in both species, loss of function mutations of EPHB4 result in specific and similar brain vascular development anomalies. Recently, EPHB4 germline mutations have been reported in non-immune hydrops fetalis and in cutaneous capillary malformation-arteriovenous malformation. Here, we show that EPHB4 mutations are also responsible for vein of Galen aneurysmal malformation, indicating that heterozygous germline mutations of EPHB4 result in a large clinical spectrum. The identification of EPHB4 pathogenic mutations in patients presenting capillary malformation or vein of Galen aneurysmal malformation should lead to careful follow-up of pregnancy of carriers for early detection of anomaly of the cerebral vasculature in order to propose optimal neonatal care. Endovascular embolization indeed greatly improved the prognosis of patients.
The induction of specific and sustainable tolerance is a challenging issue in organ transplantation. The discovery of the immunosuppressive properties of apoptotic cells in animal models has paved ...the way for their use in human transplantation. In this work, we aimed to define a stable, reproducible, and clinically compatible production procedure of human apoptotic cells (Apo-cells). Using a clinically approved extracorporeal photopheresis technique, we have produced and characterized phenotypically and functionally human apoptotic cells. These Apo-cells have immunosuppressive properties proved
and
in NOD/SCID/γC mice by their capacity to modulate an allogeneic response following both a direct and an indirect antigen presentation. These results brought the rationale for the use of Apo-cells in tolerance induction protocol for organ transplantation.
PURPOSE:This study analyses the relationship between medication use and frailty by considering the quantity of medications prescribed (polypharmacy) and the quality of medication prescribing ...(according to French criteria for Potentially Inappropriate Medications-PIMs) in people aged 65 and over.METHODS:This is a cross-sectional study based on the data from a nationally representative study about health and use of healthcare resources in France (ESPS 2012). The number of frailty criteria was assessed among exhaustion, unintentional weight loss, muscle weakness, impaired mobility, and low level of physical activity. Polypharmacy and PIMs were assessed from the data of reimbursement by the National Health Insurance over the whole year 2012. PIMs were defined according to the Laroche list plus additional criteria dealing with inappropriate prolonged use of medications. The analyses used Poisson regression models, with the number of frailty criteria as dependent variable.RESULTS:The study population was composed of 1003 women and 887 men, of mean age 74.7 +/- 7.4 years. Polypharmacy (5 to 9 drugs) and excessive polypharmacy (≥10 drugs) were reported in 42.9 and 27.4% of the study population, respectively, while 46.7% of the study population received at least one PIM during the year 2012. Polypharmacy and PIMs were both associated with the number of frailty criteria in models adjusted for socio-demographic and health characteristics of the participants. The prescription of anticholinergic medications was the only PIM that remained significantly associated with the number of frailty criteria after adjustment for polypharmacy.CONCLUSIONS:Polypharmacy and use of anticholinergic medications are independently associated with frailty in old people.
Background. Rifampicin (RIF) induces UGT1A1, an enzyme involved in raltegravir (RAL) elimination, thereby potentially lowering RAL exposure. We examined the pharmacokinetics of RAL in human ...immunodeficiency virus (HIV)–infected patients on RIF-based antitubercular therapy in the French National Agency for HIV/AIDS and Viral Hepatitis Research 12 180 Reflate Tuberculosis trial. Methods. Patients started RAL in combination with tenofovir disoproxil fumarate and lamivudine after initiation of RIF (10 mg/kg/day). In arm 1 (n = 21), they received 400 mg RAL twice daily; in arm 2 (n = 16), they received RAL 800 mg twice daily initially then 400 mg twice daily 4 weeks after RIF discontinuation. Pharmacokinetic sampling was performed over 12-hour periods, 4 weeks after initiation of RAL together with RIF (period 1), 4 weeks after RIF discontinuation (period 2), and after the RAL dose reduction in arm 2 (period 3). Results. In arm 1, the geometric mean ratio (GMR) between period 1 and period 2 was 0.94 (90% confidence interval CI, .64–1.37) for the 12-hour area under the time-concentration curve (AUC0–12), and 0.69 (90% CI, .42–1.13) for the concentration at 12 hours (C12). In arm 2, the corresponding GMRs were 0.75 (90% CI, .48–1.17) and 1.10 (90% CI, .61–2.00) for period 1 vs period 2, and 1.10 (90% CI, .78-1.55) and 1.68 (90% CI, .88–3.23) for period 1 vs period 3. Conclusions. The double dose of RAL overcompensated for RIF induction, but the standard dose was associated with only small decreases in AUC0–12 and C12 during RIF coadministration, warranting further evaluation in patients with HIV/tuberculosis coinfection. Clinical Trials Registration. NCT0082231.
Purpose
The quality of drug therapy is an important issue for nursing homes. This study aimed to assess the prevalence of polypharmacy and potentially inappropriate medications (PIMs) in a large ...sample of nursing home residents by using the data recorded during the preparation of pill dispensers.
Methods
This is a cross-sectional study that included 451 nursing homes across France. Information about the medications received by the 30,702 residents (73.8% women) living in these nursing homes was extracted from the system that assists in the preparation of pill dispensers in pharmacies. The anonymized database included age, sex, and medications prescribed to residents, as well as nursing home characteristics (capacity, legal status). Factors associated with excessive polypharmacy (≥10 different drugs) and PIMs according to the Laroche list were studied using multilevel regression models.
Results
The average number of drugs prescribed was 6.9 ± 3.3, and excessive polypharmacy concerned 21.1% of the residents (
n
= 6468). According to the Laroche list, 47.4% of residents (
n
= 14,547) received at least one PIM. Benzodiazepines (excessive doses, long-acting benzodiazepines, and combination of benzodiazepines) and anticholinergic medications (hydroxyzine, cyamemazine, alimemazine) accounted for a large part of PIMs. Individual characteristics (age, gender) influenced the risk of receiving PIMs whereas nursing home characteristics (capacity, legal status) influenced the risk of excessive polypharmacy.
Conclusions
This study shows that polypharmacy and PIMs remain highly prevalent among nursing home residents. Main PIMs concerned psychotropic and anticholinergic medications.
Spatial extension is an important characteristic for correctly associating gamma-ray-emitting sources with their counterparts at other wavelengths and for obtaining an unbiased model of their ...spectra. We present a new method for quantifying the spatial extension of sources detected by the Large Area Telescope (LAT), the primary science instrument on the Fermi Gamma-ray Space Telescope (Fermi). We perform a series of Monte Carlo simulations to validate this tool and calculate the LAT threshold for detecting the spatial extension of sources. We then test all sources in the second Fermi-LAT catalog (2FGL) for extension. We report the detection of seven new spatially extended sources.
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