Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations

PURPOSE: Predicting the phenotypic effects of mutations has become an important application in clinical genetic diagnostics. Computational tools evaluate the behavior of the variant over evolutionary time and assume that variations seen during the course of evolution are probably benign in humans. However, current tools do not take into account orthologous/paralogous relationships. Paralogs have dramatically different roles in Mendelian diseases. For example, whereas inactivating mutations in the NPC1 gene cause the neurodegenerative disorder Niemann-Pick C, inactivating mutations in its paralog NPC1L1 are not disease-causing and, moreover, are implicated in protection from coronary heart disease. METHODS: We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism’s fitness. RESULTS: Removing the paralogs and distant homologs improved the overall performance of categorizing disease-causing and benign amino acid substitutions. CONCLUSION: The results show that a thorough evolutionary analysis followed by identification of orthologs improves the accuracy in predicting disease-causing missense mutations. We anticipate that this approach will be used as a reference in the interpretation of variants in other genetic diseases as well. Genet Med 18 10, 1029–1036

An apparently normal gamma-ray burst with an unusually low luminosity

Much of progress in gamma-ray bursts has come from the studies of distant events (redshift z~1). The brightest GRBs are the most collimated events and seen across the Universe due to their brilliance. It has long been suspected that nearest (and most common) events have been missed because they are not so collimated or under-energetic or both. Here we report soft gamma-ray observations of GRB 031203, the nearest event to date (z=0.106). This event with a duration of 40 s and peak energy of >190 keV appears to be a typical long duration GRB. However, the isotropic gamma-ray energy <~10^50 erg, about three orders of magnitude smaller than the cosmological population. This event as well as the other nearby but somewhat controversial event GRB 980425 are clear outliers for the much discussed isotropic-energy peak-energy relation and luminosity spectral-lag relations. Radio calorimetry shows that both these events are under-energetic explosions. We conclude that there does indeed exist a large population of under-energetic events.Comment: 11 pages, 3 figure

The X-Ray and Radio Loud Fast Blue Optical Transient AT2020mrf: Implications for an Emerging Class of Engine-driven Massive Star Explosions

We present AT2020mrf (SRGe J154754.2+443907), an extra-galactic (z = 0.1353) fast blue optical transient (FBOT) with a rise time of t g,rise = 3.7 days and a peak luminosity of M g,peak = −20.0. Its optical spectrum around peak shows a broad (v ∼ 0.1c) emission feature on a blue continuum (T ∼ 2 × 104 K), which bears a striking resemblance to AT2018cow. Its bright radio emission (ν L ν = 1.2 × 1039 erg s−1; ν rest = 7.4 GHz; 261 days) is similar to four other AT2018cow-like events, and can be explained by synchrotron radiation from the interaction between a sub-relativistic (≳0.07-0.08c) forward shock and a dense environment ( M ̇ ≲ 10 − 3 M ⊙ yr − 1 for v w = 103 km s−1). AT2020mrf occurs in a galaxy with M * ∼ 108 M ⊙ and specific star formation rate ∼10−10 yr−1, supporting the idea that AT2018cow-like events are preferentially hosted by dwarf galaxies. The X-ray luminosity of AT2020mrf is the highest among FBOTs. At 35-37 days, SRG/eROSITA detected luminous (L X ∼ 2 × 1043 erg s−1; 0.3-10 keV) X-ray emission. The X-ray spectral shape (f ν ∝ ν −0.8) and erratic intraday variability are reminiscent of AT2018cow, but the luminosity is a factor of ∼20 greater than AT2018cow. At 328 days, Chandra detected it at L X ∼ 1042 erg s−1, which is >200 times more luminous than AT2018cow and CSS161010. At the same time, the X-ray emission remains variable on the timescale of ∼1 day. We show that a central engine, probably a millisecond magnetar or an accreting black hole, is required to power the explosion. We predict the rates at which events like AT2018cow and AT2020mrf will be detected by SRG and Einstein Probe

Improved Detection of Rare Genetic Variants for Diseases

Technology advances have promoted gene-based sequencing studies with the aim of identifying rare mutations responsible for complex diseases. A complication in these types of association studies is that the vast majority of non-synonymous mutations are believed to be neutral to phenotypes. It is thus critical to distinguish potential causative variants from neutral variation before performing association tests. In this study, we used existing predicting algorithms to predict functional amino acid substitutions, and incorporated that information into association tests. Using simulations, we comprehensively studied the effects of several influential factors, including the sensitivity and specificity of functional variant predictions, number of variants, and proportion of causative variants, on the performance of association tests. Our results showed that incorporating information regarding functional variants obtained from existing prediction algorithms improves statistical power under certain conditions, particularly when the proportion of causative variants is moderate. The application of the proposed tests to a real sequencing study confirms our conclusions. Our work may help investigators who are planning to pursue gene-based sequencing studies

Incorporating background frequency improves entropy-based residue conservation measures

BACKGROUND: Several entropy-based methods have been developed for scoring sequence conservation in protein multiple sequence alignments. High scoring amino acid positions may correlate with structurally or functionally important residues. However, amino acid background frequencies are usually not taken into account in these entropy-based scoring schemes. RESULTS: We demonstrate that using a relative entropy measure that incorporates amino acid background frequency results in improved performance in identifying functional sites from protein multiple sequence alignments. CONCLUSION: Our results suggest that the application of appropriate background frequency information may lead to more biologically relevant results in many areas of bioinformatics

Accretion Disks Around Black Holes: Twenty Five Years Later

We study the progress of the theory of accretion disks around black holes in last twenty five years and explain why advective disks are the best bet in explaining varied stationary and non-stationary observations from black hole candidates. We show also that the recently proposed advection dominated flows are incorrect.Comment: 30 Latex pages including figures. Kluwer Style files included. Appearing in `Observational Evidence for Black Holes in the Universe', ed. Sandip K. Chakrabarti, Kluwer Academic Publishers (DORDRECHT: Holland

CMB Telescopes and Optical Systems

The cosmic microwave background radiation (CMB) is now firmly established as a fundamental and essential probe of the geometry, constituents, and birth of the Universe. The CMB is a potent observable because it can be measured with precision and accuracy. Just as importantly, theoretical models of the Universe can predict the characteristics of the CMB to high accuracy, and those predictions can be directly compared to observations. There are multiple aspects associated with making a precise measurement. In this review, we focus on optical components for the instrumentation used to measure the CMB polarization and temperature anisotropy. We begin with an overview of general considerations for CMB observations and discuss common concepts used in the community. We next consider a variety of alternatives available for a designer of a CMB telescope. Our discussion is guided by the ground and balloon-based instruments that have been implemented over the years. In the same vein, we compare the arc-minute resolution Atacama Cosmology Telescope (ACT) and the South Pole Telescope (SPT). CMB interferometers are presented briefly. We conclude with a comparison of the four CMB satellites, Relikt, COBE, WMAP, and Planck, to demonstrate a remarkable evolution in design, sensitivity, resolution, and complexity over the past thirty years.Comment: To appear in: Planets, Stars and Stellar Systems (PSSS), Volume 1: Telescopes and Instrumentatio

Planck intermediate results. XLI. A map of lensing-induced B-modes

The secondary cosmic microwave background (CMB) $B$-modes stem from the post-decoupling distortion of the polarization $E$-modes due to the gravitational lensing effect of large-scale structures. These lensing-induced $B$-modes constitute both a valuable probe of the dark matter distribution and an important contaminant for the extraction of the primary CMB $B$-modes from inflation. Planck provides accurate nearly all-sky measurements of both the polarization $E$-modes and the integrated mass distribution via the reconstruction of the CMB lensing potential. By combining these two data products, we have produced an all-sky template map of the lensing-induced $B$-modes using a real-space algorithm that minimizes the impact of sky masks. The cross-correlation of this template with an observed (primordial and secondary) $B$-mode map can be used to measure the lensing $B$-mode power spectrum at multipoles up to $2000$. In particular, when cross-correlating with the $B$-mode contribution directly derived from the Planck polarization maps, we obtain lensing-induced $B$-mode power spectrum measurement at a significance level of $12\,\sigma$, which agrees with the theoretical expectation derived from the Planck best-fit $\Lambda$CDM model. This unique nearly all-sky secondary $B$-mode template, which includes the lensing-induced information from intermediate to small ($10\lesssim \ell\lesssim 1000$) angular scales, is delivered as part of the Planck 2015 public data release. It will be particularly useful for experiments searching for primordial $B$-modes, such as BICEP2/Keck Array or LiteBIRD, since it will enable an estimate to be made of the lensing-induced contribution to the measured total CMB $B$-modes.Comment: 20 pages, 12 figures; Accepted for publication in A&A; The B-mode map is part of the PR2-2015 Cosmology Products; available as Lensing Products in the Planck Legacy Archive http://pla.esac.esa.int/pla/#cosmology; and described in the 'Explanatory Supplement' https://wiki.cosmos.esa.int/planckpla2015/index.php/Specially_processed_maps#2015_Lensing-induced_B-mode_ma

SRG/ART-XC discovery of SRGA J204318.2+443815: Towards the complete population of faint X-ray pulsars

We report the discovery of the new long-period X-ray pulsar SRGA J204318.2+443815/SRGe J204319.0+443820 in a Be binary system. The source was found in the second all-sky survey by the Mikhail Pavlinsky ART-XC telescope on board the SRG mission. The followup observations with XMM-Newton, NICER, and NuSTAR allowed us to discover a strong coherent signal in the source light curve with a period of ~742 s. The pulsed fraction was found to depend on an increase in energy from ~20% in soft X-rays to >50% at high energies, as is typical for X-ray pulsars. The source has a quite hard spectrum with an exponential cutoff at high energies and a bolometric luminosity of Lx ≃ 4 x 1035 erg s-1. The X-ray position of the source is found to be consistent with the optical transient ZTF18abjpmzf, located at a distance of ~8.0 kpc. Dedicated optical and infrared observations with the RTT-150, NOT, Keck, and Palomar telescopes revealed a number of emission lines (Hα, He I, and the Paschen and Braket series) with a strongly absorbed continuum. According to the SRG scans and archival XMM-Newton data, the source flux is moderately variable (by a factor of 4-10) on timescales of several months and years. All this suggests that SRGA J204318.2+443815/SRGe J204319.0+443820 is a new quasipersistent low-luminosity X-ray pulsar in a distant binary system with a Be-star of the B0-B2e class. Thus the SRG observatory allowed us to unveil a hidden population of faint objects, including a population of slowly rotating X-ray pulsars in Be systems.</p

Pre-Existing T- and B-Cell Defects in One Progressive Multifocal Leukoencephalopathy Patient

Progressive multifocal leukoencephalopathy (PML) usually occurs in patients with severe immunosuppression, hematological malignancies, chronic inflammatory conditions or receiving organ transplant. Recently, PML has also been observed in patients treated with monoclonal antibodies. By taking advantage of the availability of samples from a multiple sclerosis (MS) patient treated with natalizumab, the antibody anti-α4 integrin, who developed PML and was monitored starting before therapy initiation, we investigated the fate of T and B lymphocytes in the onset of PML. Real-time PCR was used to measure new T- and B-cell production by means of T-cell receptor excision circle (TREC) and K-deleting recombination excision circle (KREC) analysis and to quantify transcripts for CD34, terminal-deoxynucleotidyltransferase, and V pre-B lymphocyte gene 1. T- and B-cell subsets and T-cell heterogeneity were measured by flow cytometry and spectratyping. The data were compared to those of untreated and natalizumab-treated MS patients and healthy donors. Before therapy, a patient who developed PML had a low TREC and KREC number; TRECs remained low, while KRECs and pre-B lymphocyte gene 1 transcripts peaked at 6 months of therapy and then decreased at PML diagnosis. Flow cytometry confirmed the deficient number of newly produced T lymphocytes, counterbalanced by an increase in TEMRA cells. The percentage of naive B cells increased by approximately 70% after 6 months of therapy, but B lymphocyte number remained low for the entire treatment period. T-cell heterogeneity and immunoglobulins were reduced