A Theoretical Model for the Mbh−σM_{\rm bh}-\sigma Relation for Supermassive Black Holes in Galaxies

We construct a model for the formation of black holes within galactic bulges. The initial state is a slowly rotating isothermal sphere, characterized by effective transport speed \aeff and rotation rate $\Omega$. The black hole mass is determined when the centrifugal radius of the collapse flow exceeds the capture radius of the central black hole. This model reproduces the observed correlation between black hole masses and galactic velocity dispersions, \mbh \approx 10^8 M_\odot (\sigma/200 \kms)^4, where \sigma = \sqrt{2} \aeff. This model also predicts the ratio \mrat of black hole mass to host mass: \mrat $\approx$ 0.004 (\sigma/200 \kms).Comment: 9 pages, 2 figures, submitted to Astrophysical Journal Letter

Multiwaveband analysis of brightest GRB070125

We present a comprehensive multiwavelength analysis of the bright, long duration gamma-ray burst GRB 070125, comprised of observations in gamma-ray, X-ray, optical, millimeter and centimeter wavebands. Radio light curves show rapid flux variations, which are interpreted as due to interstellar scintillation, and are used to derive an upper limit of 2.4×10^17 cm on the radius of the fireball. Radio light curves and spectra suggest that the afterglow shock wave is moving in a dense medium. Our broadband modeling favors a constant density profile for the circumburst medium over a wind-like profile (R^−2). GRB 070125 is a burst with high radiative efficiency (>60%)

Microcanonical treatment of black hole decay at the Large Hadron Collider

This study of corrections to the canonical picture of black hole decay in large extra dimensions examines the effects of back-reaction corrected and microcanonical emission at the LHC. We provide statistical interpretations of the different multiparticle number densities in terms of black hole decay to standard model particles. Provided new heavy particles of mass near the fundamental Planck scale are not discovered, differences between these corrections and thermal decay will be insignificant at the LHC.Comment: small additions and clarifications, format for J. Phys.

Evidence of Widespread Selection on Standing Variation in Europe at Height-Associated SNPs

Strong signatures of positive selection at newly arising genetic variants are well-documented in humans, but this form of selection may not be widespread in recent human evolution. Because many human traits are highly polygenic and partly determined by common, ancient genetic variation, an alternative model for rapid genetic adaptation has been proposed: weak selection acting on many pre-existing (standing) genetic variants, or polygenic adaptation. By studying height, a classic polygenic trait, we demonstrate the first human signature of widespread selection on standing variation. We show that frequencies of alleles associated with increased height, both at known loci and genome-wide, are systematically elevated in Northern Europeans compared with Southern Europeans $(p<4.3×10^{−4})$. This pattern mirrors intra-European height differences and is not confounded by ancestry or other ascertainment biases. The systematic frequency differences are consistent with the presence of widespread weak selection (selection coefficients $~10^{−3}–10^{−5}$ per allele) rather than genetic drift alone $(p<10^{−15})$

Viral Sequestration of Antigen Subverts Cross Presentation to CD8+ T Cells

Virus-specific CD8+ T cells (TCD8+) are initially triggered by peptide-MHC Class I complexes on the surface of professional antigen presenting cells (pAPC). Peptide-MHC complexes are produced by two spatially distinct pathways during virus infection. Endogenous antigens synthesized within virus-infected pAPC are presented via the direct-presentation pathway. Many viruses have developed strategies to subvert direct presentation. When direct presentation is blocked, the cross-presentation pathway, in which antigen is transferred from virus-infected cells to uninfected pAPC, is thought to compensate and allow the generation of effector TCD8+. Direct presentation of vaccinia virus (VACV) antigens driven by late promoters does not occur, as an abortive infection of pAPC prevents production of these late antigens. This lack of direct presentation results in a greatly diminished or ablated TCD8+ response to late antigens. We demonstrate that late poxvirus antigens do not enter the cross-presentation pathway, even when identical antigens driven by early promoters access this pathway efficiently. The mechanism mediating this novel means of viral modulation of antigen presentation involves the sequestration of late antigens within virus factories. Early antigens and cellular antigens are cross-presented from virus-infected cells, as are late antigens that are targeted to compartments outside of the virus factories. This virus-mediated blockade specifically targets the cross-presentation pathway, since late antigen that is not cross-presented efficiently enters the MHC Class II presentation pathway. These data are the first to describe an evasion mechanism employed by pathogens to prevent entry into the cross-presentation pathway. In the absence of direct presentation, this evasion mechanism leads to a complete ablation of the TCD8+ response and a potential replicative advantage for the virus. Such mechanisms of viral modulation of antigen presentation must also be taken into account during the rational design of antiviral vaccines

Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2

Acknowledgements The authors would like to acknowledge Dr David A. Blizard for his role in the development of the ideas that led to this study and feedback on the manuscript, Professor Helen Macdonald for valuable advice on study design, Dr Leslie R. Noble for help with the UK Biobank data, and Dr Joseph P. Gyekis for help genotyping cohort 2 mice. The authors would like to acknowledge funding from the University of Aberdeen for the Maxwell computer cluster, the Elphinstone and IMS studentship for AIHC; a Schweppe Foundation Career Development Award (AAP), and the NIH (NIAMS (AL: R01AR056280) and NIDA (AAP:R01DA021336, AAP:R21DA024845, AAP:T32MH020065, NMG:F31DA03635803), NIGMS (NMG:T32GM007197), NHGRI (MA:R01HG002899))Peer reviewedPostprin

Constraints to Implementing the Essential Health Package in Malawi

Increasingly seen as a useful tool of health policy, Essential or Minimal Health Packages direct resources to interventions that aim to address the local burden of disease and be cost-effective. Less attention has been paid to the delivery mechanisms for such interventions. This study aimed to assess the degree to which the Essential Health Package (EHP) in Malawi was available to its population and what health system constraints impeded its full implementation. The first phase of this study comprised a survey of all facilities in three districts including interviews with all managers and clinical staff. In the second and third phase, results were discussed with District Health Management Teams and national level stakeholders, respectively, including representatives of the Ministry of Health, Central Medical Stores, donors and NGOs. The EHP in Malawi is focussing on the local burden of disease; however, key constraints to its successful implementation included a widespread shortage of staff due to vacancies but also caused by frequent trainings and meetings (only 48% of expected man days of clinical staff were available; training and meetings represented 57% of all absences in health centres). Despite the training, the percentage of health workers aware of vital diagnostic and therapeutic approaches to EHP conditions was weak. Another major constraint was shortages of vital drugs at all levels of facilities (e.g. Cotrimoxazole was sufficiently available to treat the average number of patients in only 27% of health centres). Although a few health workers noted some improvement in infrastructure and working conditions, they still considered them to be widely inadequate. In Malawi, as in similar resource poor countries, greater attention needs to be given to the health system constraints to delivering health care. Removal of these constraints should receive priority over the considerable focus on the development and implementation of essential packages of interventions

Note on non-Abelian two-form gauge fields

Motivated by application to multiple M5 branes, we study some properties of non-Abelian two-form gauge theories. We note that the fake curvature condition which is commonly used in the literature would restrict the dynamics to be either a free theory or a topological system. We then propose a modification of transformation law which simplifies the gauge transformation of 3-form field strength and enables us to write down a gauge invariant action. We then argue that a generalization of Stueckelberg mechanism naturally gives mass to the two-form gauge field. For the application to multiple M5-branes, it should be identified with the KK modes.Comment: 21 page

Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8(+) T cells

Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8(+) T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4(+)CD25(+) regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8(+) T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The γ (C) cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of γ (C) cytokine–responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8(+) T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells

Topological Orthoalgebras

We define topological orthoalgebras (TOAs) and study their properties. While every topological orthomodular lattice is a TOA, the lattice of projections of a Hilbert space is an example of a lattice-ordered TOA that is not a toplogical lattice. On the other hand, we show that every compact Boolean TOA is a topological Boolean algebra. We also show that a compact TOA in which 0 is an isolated point is atomic and of finite height. We identify and study a particularly tractable class of TOAs, which we call {\em stably ordered}: those in which the upper-set generated by an open set is open. This includes all topological OMLs, and also the projection lattices of Hilbert spaces. Finally, we obtain a topological version of the Foulis-Randall representation theory for stably ordered TOAsComment: 16 pp, LaTex. Minor changes and corrections in sections 1; more substantial corrections in section