Constraints on the Progenitor System of the Type Ia Supernova SN 2011fe/PTF11kly

Type Ia supernovae (SNe) serve as a fundamental pillar of modern cosmology, owing to their large luminosity and a well-defined relationship between light-curve shape and peak brightness. The precision distance measurements enabled by SNe Ia first revealed the accelerating expansion of the universe, now widely believed (though hardly understood) to require the presence of a mysterious "dark" energy. General consensus holds that Type Ia SNe result from thermonuclear explosions of a white dwarf (WD) in a binary system; however, little is known of the precise nature of the companion star and the physical properties of the progenitor system. Here we make use of extensive historical imaging obtained at the location of SN 2011fe/PTF11kly, the closest SN Ia discovered in the digital imaging era, to constrain the visible-light luminosity of the progenitor to be 10-100 times fainter than previous limits on other SN Ia progenitors. This directly rules out luminous red giants and the vast majority of helium stars as the mass-donating companion to the exploding white dwarf. Any evolved red companion must have been born with mass less than 3.5 times the mass of the Sun. These observations favour a scenario where the exploding WD of SN 2011fe/PTF11kly, accreted matter either from another WD, or by Roche-lobe overflow from a subgiant or main-sequence companion star.Comment: 22 pages, 6 figures, submitte

Asymmetric recurrent laryngeal nerve conduction velocities and dorsal cricoarytenoid muscle electromyographic characteristics in clinically normal horses

The dorsal cricoarytenoid (DCA) muscles, are a fundamental component of the athletic horse’s respiratory system: as the sole abductors of the airways, they maintain the size of the rima glottis which is essential for enabling maximal air intake during intense exercise. Dysfunction of the DCA muscle leads to arytenoid collapse during exercise, resulting in poor performance. An electrodiagnostic study including electromyography of the dorsal cricoarytenoid muscles and conduction velocity testing of the innervating recurrent laryngeal nerves (RLn) was conducted in horses with normal laryngeal function. We detected reduced nerve conduction velocity of the left RLn, compared to the right, and pathologic spontaneous activity (PSA) of myoelectrical activity within the left DCA muscle in half of this horse population and the horses with the slowest nerve conduction velocities. The findings in this group of horses are consistent with left sided demyelination and axonal loss, consistent with Recurrent Laryngeal Neuropathy (RLN), a highly prevalent degenerative disorder of the RLn in horses that predominantly affects the left side. The detection of electromyographic changes compatible with RLN in clinically unaffected horses is consistent with previous studies that identified “subclinical” subjects, presenting normal laryngeal function despite neuropathologic changes within nerve and muscle confirmed histologically

The Effect of Predictability on Subjective Duration

Events can sometimes appear longer or shorter in duration than other events of equal length. For example, in a repeated presentation of auditory or visual stimuli, an unexpected object of equivalent duration appears to last longer. Illusions of duration distortion beg an important question of time representation: when durations dilate or contract, does time in general slow down or speed up during that moment? In other words, what entailments do duration distortions have with respect to other timing judgments? We here show that when a sound or visual flicker is presented in conjunction with an unexpected visual stimulus, neither the pitch of the sound nor the frequency of the flicker is affected by the apparent duration dilation. This demonstrates that subjective time in general is not slowed; instead, duration judgments can be manipulated with no concurrent impact on other temporal judgments. Like spatial vision, time perception appears to be underpinned by a collaboration of separate neural mechanisms that usually work in concert but are separable. We further show that the duration dilation of an unexpected stimulus is not enhanced by increasing its saliency, suggesting that the effect is more closely related to prediction violation than enhanced attention. Finally, duration distortions induced by violations of progressive number sequences implicate the involvement of high-level predictability, suggesting the involvement of areas higher than primary visual cortex. We suggest that duration distortions can be understood in terms of repetition suppression, in which neural responses to repeated stimuli are diminished

Human Metapneumovirus Glycoprotein G Inhibits Innate Immune Responses

Human metapneumovirus (hMPV) is a leading cause of acute respiratory tract infection in infants, as well as in the elderly and immunocompromised patients. No effective treatment or vaccine for hMPV is currently available. A recombinant hMPV lacking the G protein (rhMPV-ΔG) was recently developed as a potential vaccine candidate and shown to be attenuated in the respiratory tract of a rodent model of infection. The mechanism of its attenuation, as well as the role of G protein in modulation of hMPV-induced cellular responses in vitro, as well as in vivo, is currently unknown. In this study, we found that rhMPV-ΔG-infected airway epithelial cells produced higher levels of chemokines and type I interferon (IFN) compared to cells infected with rhMPV-WT. Infection of airway epithelial cells with rhMPV-ΔG enhanced activation of transcription factors belonging to the nuclear factor (NF)-κB and interferon regulatory factor (IRF) families, as revealed by increased nuclear translocation and/or phosphorylation of these transcription factors. Compared to rhMPV-WT, rhMPV-ΔG also increased IRF- and NF-κB-dependent gene transcription, which was reversely inhibited by G protein expression. Since RNA helicases have been shown to play a fundamental role in initiating viral-induced cellular signaling, we investigated whether retinoic induced gene (RIG)-I was the target of G protein inhibitory activity. We found that indeed G protein associated with RIG-I and inhibited RIG-I-dependent gene transcription, identifying an important mechanism by which hMPV affects innate immune responses. This is the first study investigating the role of hMPV G protein in cellular signaling and identifies G as an important virulence factor, as it inhibits the production of important immune and antiviral mediators by targeting RIG-I, a major intracellular viral RNA sensor

Hepatitis B Virus Impairs TLR9 Expression and Function in Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs) play a key role in detecting pathogens by producing large amounts of type I interferon (IFN) by sensing the presence of viral infections through the Toll-Like Receptor (TLR) pathway. TLR9 is a sensor of viral and bacterial DNA motifs and activates the IRF7 transcription factor which leads to type I IFN secretion by pDCs. However, during chronic hepatitis B virus (HBV) infection, pDCs display an impaired ability to secrete IFN-α following ex vivo stimulation with TLR9 ligands. Here we highlight several strategies used by HBV to block IFN-α production through a specific impairment of the TLR9 signaling. Our results show that HBV particle internalisation could inhibit TLR9- but not TLR7-mediated secretion of IFN-α by pDCs. We observed that HBV down-regulated TLR9 transcriptional activity in pDCs and B cells in which TLR9 mRNA and protein levels were reduced. HBV can interfere with TLR9 activity by blocking the MyD88-IRAK4 axis and Sendai virus targeting IRF7 to block IFN-α production. Neutralising CpG motif sequences were identified within HBV DNA genome of genotypes A to H which displayed a suppressive effect on TLR9-immune activation. Moreover, TLR9 mRNA and protein were downregulated in PBMCs from patients with HBV-associated chronic hepatitis and hepatocellular carcinoma. Thus HBV has developed several escape mechanisms to avoid TLR9 activation in both pDCs and B lymphocytes, which may in turn contribute to the establishment and/or persistence of chronic infection

Viral Capsid Is a Pathogen-Associated Molecular Pattern in Adenovirus Keratitis

Human adenovirus (HAdV) infection of the human eye, in particular serotypes 8, 19 and 37, induces the formation of corneal subepithelial leukocytic infiltrates. Using a unique mouse model of adenovirus keratitis, we studied the role of various virus-associated molecular patterns in subsequent innate immune responses of resident corneal cells to HAdV-37 infection. We found that neither viral DNA, viral gene expression, or viral replication was necessary for the development of keratitis. In contrast, empty viral capsid induced keratitis and a chemokine profile similar to intact virus. Transfected viral DNA did not induce leukocyte infiltration despite CCL2 expression similar to levels in virus infected corneas. Mice without toll-like receptor 9 (Tlr9) signaling developed clinical keratitis upon HAdV-37 infection similar to wild type mice, although the absolute numbers of activated monocytes in the cornea were less in Tlr9−/− mice. Virus induced leukocytic infiltrates and chemokine expression in mouse cornea could be blocked by treatment with a peptide containing arginine glycine aspartic acid (RGD). These results demonstrate that adenovirus infection of the cornea induces chemokine expression and subsequent infiltration by leukocytes principally through RGD contact between viral capsid and the host cell, possibly through direct interaction between the viral capsid penton base and host cell integrins

MyD88 and STING Signaling Pathways Are Required for IRF3-Mediated IFN-β Induction in Response to Brucella abortus Infection

Type I interferons (IFNs) are cytokines that orchestrate diverse immune responses to viral and bacterial infections. Although typically considered to be most important molecules in response to viruses, type I IFNs are also induced by most, if not all, bacterial pathogens. In this study, we addressed the role of type I IFN signaling during Brucella abortus infection, a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. Herein, we have shown that B. abortus induced IFN-β in macrophages and splenocytes. Further, IFN-β induction by Brucella was mediated by IRF3 signaling pathway and activates IFN-stimulated genes via STAT1 phosphorylation. In addition, IFN-β expression induced by Brucella is independent of TLRs and TRIF signaling but MyD88-dependent, a pathway not yet described for Gram-negative bacteria. Furthermore, we have identified Brucella DNA as the major bacterial component to induce IFN-β and our study revealed that this molecule operates through a mechanism dependent on RNA polymerase III to be sensed probably by an unknown receptor via the adaptor molecule STING. Finally, we have demonstrated that IFN-αβR KO mice are more resistant to infection suggesting that type I IFN signaling is detrimental to host control of Brucella. This resistance phenotype is accompanied by increased IFN-γ and NO production by IFN-αβR KO spleen cells and reduced apoptosis

Cross-oncopanel study reveals high sensitivity and accuracy with overall analytical performance depending on genomic regions

BackgroundTargeted sequencing using oncopanels requires comprehensive assessments of accuracy and detection sensitivity to ensure analytical validity. By employing reference materials characterized by the U.S. Food and Drug Administration-led SEquence Quality Control project phase2 (SEQC2) effort, we perform a cross-platform multi-lab evaluation of eight Pan-Cancer panels to assess best practices for oncopanel sequencing.ResultsAll panels demonstrate high sensitivity across targeted high-confidence coding regions and variant types for the variants previously verified to have variant allele frequency (VAF) in the 5-20% range. Sensitivity is reduced by utilizing VAF thresholds due to inherent variability in VAF measurements. Enforcing a VAF threshold for reporting has a positive impact on reducing false positive calls. Importantly, the false positive rate is found to be significantly higher outside the high-confidence coding regions, resulting in lower reproducibility. Thus, region restriction and VAF thresholds lead to low relative technical variability in estimating promising biomarkers and tumor mutational burden.ConclusionThis comprehensive study provides actionable guidelines for oncopanel sequencing and clear evidence that supports a simplified approach to assess the analytical performance of oncopanels. It will facilitate the rapid implementation, validation, and quality control of oncopanels in clinical use.Peer reviewe

The role of unintegrated DNA in HIV infection

Integration of the reverse transcribed viral genome into host chromatin is the hallmark of retroviral replication. Yet, during natural HIV infection, various unintegrated viral DNA forms exist in abundance. Though linear viral cDNA is the precursor to an integrated provirus, increasing evidence suggests that transcription and translation of unintegrated DNAs prior to integration may aid productive infection through the expression of early viral genes. Additionally, unintegrated DNA has the capacity to result in preintegration latency, or to be rescued and yield productive infection and so unintegrated DNA, in some circumstances, may be considered to be a viral reservoir. Recently, there has been interest in further defining the role and function of unintegrated viral DNAs, in part because the use of anti-HIV integrase inhibitors leads to an abundance of unintegrated DNA, but also because of the potential use of non-integrating lentiviral vectors in gene therapy and vaccines. There is now increased understanding that unintegrated viral DNA can either arise from, or be degraded through, interactions with host DNA repair enzymes that may represent a form of host antiviral defence. This review focuses on the role of unintegrated DNA in HIV infection and additionally considers the potential implications for antiviral therapy

Dark Matter in the Milky Way's Dwarf Spheroidal Satellites

The Milky Way's dwarf spheroidal satellites include the nearest, smallest and least luminous galaxies known. They also exhibit the largest discrepancies between dynamical and luminous masses. This article reviews the development of empirical constraints on the structure and kinematics of dSph stellar populations and discusses how this phenomenology translates into constraints on the amount and distribution of dark matter within dSphs. Some implications for cosmology and the particle nature of dark matter are discussed, and some topics/questions for future study are identified.Comment: A version with full-resolution figures is available at http://www.cfa.harvard.edu/~mwalker/mwdsph_review.pdf; 70 pages, 22 figures; invited review article to be published in Vol. 5 of the book "Planets, Stars, and Stellar Systems", published by Springe