An automated stochastic approach to the identification of the protein specificity determinants and functional subfamilies

<p>Abstract</p> <p>Background</p> <p>Recent progress in sequencing and 3 D structure determination techniques stimulated development of approaches aimed at more precise annotation of proteins, that is, prediction of exact specificity to a ligand or, more broadly, to a binding partner of any kind.</p> <p>Results</p> <p>We present a method, SDPclust, for identification of protein functional subfamilies coupled with prediction of specificity-determining positions (SDPs). SDPclust predicts specificity in a phylogeny-independent stochastic manner, which allows for the correct identification of the specificity for proteins that are separated on a phylogenetic tree, but still bind the same ligand. SDPclust is implemented as a Web-server <url>http://bioinf.fbb.msu.ru/SDPfoxWeb/</url> and a stand-alone Java application available from the website.</p> <p>Conclusions</p> <p>SDPclust performs a simultaneous identification of specificity determinants and specificity groups in a statistically robust and phylogeny-independent manner.</p

MAGIC observations of very high energy gamma-rays from HESS J1813-178

Recently, the HESS collaboration has reported the detection of gamma-ray emission above a few hundred GeV from eight new sources located close to the Galactic Plane. The source HESS J1813-178 has sparked particular interest, as subsequent radio observations imply an association with SNR G12.82-0.02. Triggered by the detection in VHE gamma-rays, a positionally coincident source has also been found in INTEGRAL and ASCA data. In this Letter we present MAGIC observations of HESS J1813-178, resulting in the detection of a differential gamma-ray flux consistent with a hard-slope power law, described as dN/(dA dt dE) = (3.3+/-0.5)*10^{-12} (E/TeV)^{-2.1+/-0.2} cm^(-2)s^(-1)TeV^(-1). We briefly discuss the observational technique used, the procedure implemented for the data analysis, and put this detection in the perspective of multifrequency observations.Comment: Accepted by ApJ Letter

Variable Very High Energy Gamma-ray Emission from the Microquasar LS I +61 303

Microquasars are binary star systems with relativistic radio-emitting jets. They are potential sources of cosmic rays and laboratories for elucidating the physics of relativistic jets. Here we report the detection of variable gamma-ray emission above 100 gigaelectron volts from the microquasar LS I +61 303. Six orbital cycles were recorded. Several detections occur at a similar orbital phase, suggesting the emission is periodic. The strongest gamma-ray emission is not observed when the two stars are closest to one another, implying a strong orbital modulation of the emission or the absorption processes.Comment: 11 pages with 4 figure

Variable Very High Energy Gamma-ray Emission from the Microquasar LS I +61 303

Microquasars are binary star systems with relativistic radio-emitting jets. They are potential sources of cosmic rays and laboratories for elucidating the physics of relativistic jets. Here we report the detection of variable gamma-ray emission above 100 gigaelectron volts from the microquasar LS I +61 303. Six orbital cycles were recorded. Several detections occur at a similar orbital phase, suggesting the emission is periodic. The strongest gamma-ray emission is not observed when the two stars are closest to one another, implying a strong orbital modulation of the emission or the absorption processes.Comment: 11 pages with 4 figure

Observation of VHE Gamma Radiation from HESS J1834-087/W41 with the MAGIC Telescope

Recently, the HESS array has reported the detection of gamma-ray emission above a few hundred GeV from eight new sources located close to the Galactic Plane. The source HESS J1834-087 is spatially coincident with SNR G23.3-0.3 (W41). Here we present MAGIC observations of this source, resulting in the detection of a differential gamma-ray flux consistent with a power law, described as dN/(dA dt dE) = (3.7 +/- 0.6)*10^(-12) (E/TeV)^(-2.5 +/- 0.2) \ cm^(-2)s^(-1)TeV^(-1). We confirm the extended character of this flux. We briefly discuss the observational technique used, the procedure implemented for the data analysis, and put this detection in the perspective of the molecular environment found in the region of W41. We present 13CO and 12CO emission maps showing the existence of a massive molecular cloud in spatial superposition with the MAGIC detection.Comment: Accepted by ApJ Letter

Observation of VHE gamma-ray emission from the Active Galactic Nucleus 1ES1959+650 using the MAGIC telecope

The MAGIC Cherenkov telescope has observed very high energy (VHE) gamma-ray emission from the Active Galactic Nucleus 1ES1959+650 during six hours in September and October 2004. The observations were carried out alternated with the Crab Nebula, whose data were used as reference source for optimizing gamma/hadron separation and for flux comparison. The data analysis shows VHE gamma-ray emission of 1ES1959+650 with ~ 8 sigma significance, at a time of low activity in both optical and X-ray wavelengths. An integral flux above ~ 180 GeV of about 20% of the Crab was obtained. The light curve, sampled over 7 days, shows no significant variations. The differential energy spectrum between 180 GeV and 2 TeV can be fitted with a power law of index -2.72 +/- 0.14. The spectrum is consistent with the slightly steeper spectrum seen by HEGRA at higher energies, also during periods of low X-ray activity.Comment: 16 pages, 6 figure

Observation of Gamma Rays from the Galactic Center with the MAGIC Telescope

Recently, the Galactic Center has been reported to be a source of very high energy (VHE) gamma-rays by the VERITAS, CANGAROO and HESS experiments. The energy spectra as measured by these experiments show substantial differences. In this Letter we present MAGIC observations of the Galactic Center, resulting in the detection of a differential gamma-ray flux consistent with a steady, hard-slope power law, described as dN/(dA dt dE) = (2.9+/-0.6)*10^{-12} (E/TeV)^{-2.2+/-0.2} cm^{-2}s^{-1}TeV^{-1}. The gamma-ray source is centered at (Ra, Dec)=(17h 45m 20s, -29deg 2'. This result confirms the previous measurements by the HESS experiment and indicates a steady source of TeV gamma-rays. We briefly describe the observational technique used, the procedure implemented for the data analysis, and discuss the results in the perspective of different models proposed for the acceleration of the VHE gamma-rays.Comment: ApJL submitte

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Meglumin acridonacetate to treat COVID-19: Prospect of using

The use of interferon drugs against COVID-19 is based on С level of evidence and analogies with efficacy against other coronaviruses. The interferon inductor meglumin acridonacetate (Cycloferon) has an advantageous safety profile and phar-maco-economic advantages, which makes it possible to consider its probable use against SARS-CoV-2. In this review, both the evidence of the effectiveness of interferons against coronaviruses and the arguments in favor of the effectiveness of Cycloferon against the same pathogens are systematized. The arguments of pharmacodynamic, biochemical, pathophysiological experimental and clinical plan in favor of Cycloferon are presented