On the Nature of MeV-blazars

Broad-band spectra of the FSRQ (flat-spectrum-radio quasars) detected in the high energy gamma-ray band imply that there may be two types of such objects: those with steep gamma-ray spectra, hereafter called MeV-blazars, and those with flat gamma-ray spectra, GeV-blazars. We demonstrate that this difference can be explained in the context of the ERC (external-radiation-Compton) model using the same electron injection function. A satisfactory unification is reachable, provided that: (a) spectra of GeV-blazars are produced by internal shocks formed at the distances where cooling of relativistic electrons in a jet is dominated by Comptonization of broad emission lines, whereas spectra of MeV-blazars are produced at the distances where cooling of relativistic electrons is dominated by Comptonization of near-IR radiation from hot dust; (b) electrons are accelerated via a two step process and their injection function takes the form of a double power-law, with the break corresponding to the threshold energy for the diffusive shock acceleration. Direct predictions of our model are that, on average, variability time scales of the MeV-blazars should be longer than variability time scales of the GeV-blazars, and that both types of the blazar phenomenon can appear in the same object.Comment: Accepted for publication in the Astrophysical Journa

Novel Glycopolymer Eradicates Antibiotic- and CCCP-Induced Persister Cells in Pseudomonas aeruginosa

Antibiotic treatments often fail to completely eradicate a bacterial infection, leaving behind an antibiotic-tolerant subpopulation of intact bacterial cells called persisters. Persisters are considered a major cause for treatment failure and are thought to greatly contribute to the recalcitrance of chronic infections. Pseudomonas aeruginosa infections are commonly associated with elevated levels of drug-tolerant persister cells, posing a serious threat to human health. This study represents the first time a novel large molecule polycationic glycopolymer, poly (acetyl, arginyl) glucosamine (PAAG), has been evaluated against antibiotic and carbonyl cyanide m-chlorophenylhydrazone induced P. aeruginosa persisters. PAAG eliminated eliminated persisters at concentrations that show no significant cytotoxicity on human lung epithelial cells. PAAG demonstrated rapid bactericidal activity against both forms of induced P. aeruginosa persister cells resulting in complete eradication of the in vitro persister cells within 24 h of treatment. PAAG demonstrated greater efficacy against persisters in vitro than antibiotics currently being used to treat persistent chronic infections such as tobramycin, colistin, azithromycin, aztreonam, and clarithromycin. PAAG caused rapid permeabilization of the cell membrane and caused significant membrane depolarization in persister cells. PAAG efficacy against these bacterial subpopulations suggests it may have substantial therapeutic potential for eliminating recurrent P. aeruginosa infections

The Formation of the First Massive Black Holes

Supermassive black holes (SMBHs) are common in local galactic nuclei, and SMBHs as massive as several billion solar masses already exist at redshift z=6. These earliest SMBHs may grow by the combination of radiation-pressure-limited accretion and mergers of stellar-mass seed BHs, left behind by the first generation of metal-free stars, or may be formed by more rapid direct collapse of gas in rare special environments where dense gas can accumulate without first fragmenting into stars. This chapter offers a review of these two competing scenarios, as well as some more exotic alternative ideas. It also briefly discusses how the different models may be distinguished in the future by observations with JWST, (e)LISA and other instruments.Comment: 47 pages with 306 references; this review is a chapter in "The First Galaxies - Theoretical Predictions and Observational Clues", Springer Astrophysics and Space Science Library, Eds. T. Wiklind, V. Bromm & B. Mobasher, in pres

Initial clinical experience with frameless optically guided stereotactic radiosurgery/radiotherapy in pediatric patients

The objective of this study is to report our initial experience treating pediatric patients with central nervous system tumors using a frameless, optically guided linear accelerator. Pediatric patients were selected for treatment after evaluation by a multidisciplinary neuro-oncology team including neurosurgery, neurology, pathology, oncology, and radiation oncology. Prior to treatment, all patients underwent treatment planning using magnetic resonance imaging (MRI) and treatment simulation on a standard computed tomography scanner (CT). For CT simulation, patients were fitted with a customized plastic face mask with a bite block attached to an optical array with four reflective markers. After ensuring adequate reproducibility, these markers were tracked during treatment by an infra-red camera. All treatments were delivered on a Varian Trilogy linear accelerator. The follow-up period ranges from 1–18 months, with a median follow-up of 6 months. Nine patients, ages ranging from 12 to 19 years old (median age 15 years old), with a variety of tumors have been treated. Patients were treated for juvenile pilocytic astrocytoma (JPA; n = 2), pontine low-grade astrocytoma (n = 1), pituitary adenoma (n = 3), metastatic medulloblastoma (n = 1), acoustic neuroma (n = 1), and pineocytoma (n = 1). We followed patients for a median of 12 months (range 3–18 months) with no in-field failures and were able to obtain encouraging toxicity profiles. Frameless stereotactic optically guided radiosurgery and radiotherapy provides a feasible and accurate tool to treat a number of benign and malignant tumors in children with minimal treatment-related morbidity

High-redshift formation and evolution of central massive objects II: The census of BH seeds

We present results of simulations aimed at tracing the formation of nuclear star clusters (NCs) and black hole (BH) seeds, in a cosmological context. We focus on two mechanisms for the formation of BHs at high redshifts: as end-products of (1) Population III stars in metal free halos, and of (2) runaway stellar collisions in metal poor NCs. Our model tracks the chemical, radiative and mechanical feedback of stars on the baryonic component of the evolving halos. This procedure allows us to evaluate when and where the conditions for BH formation are met, and to trace the emergence of BH seeds arising from the dynamical channel, in a cosmological context. BHs start to appear already at z~30 as remnants of Population III stars. The efficiency of this mechanism begins decreasing once feedbacks become increasingly important. Around redshift z~15, BHs mostly form in the centre of mildly metal enriched halos inside dense NCs. The seed BHs that form along the two pathways have at birth a mass around 100-1000M\odot. The occupation fraction of BHs is a function of both halo mass and mass growth rate: at a given z, heavier and faster growing halos have a higher chance to form a native BH, or to acquire an inherited BH via merging of another system. With decreasing z, the probability of finding a BH shifts toward progressively higher mass halo intervals. This is due to the fact that, at later cosmic times, low mass systems rarely form a seed, and already formed BHs are deposited into larger mass systems due to hierarchical mergers. Our model predict that at z=0, all halos above 10^11M\odot should host a BH (in agreement with observational results), most probably inherited during their lifetime. Halos less massive then 10^9M\odot have a higher probability to host a native BH, but their occupation fraction decreases below 10%.Comment: 12 pages, MNRAS, accepte

Genetic Signatures of Exceptional Longevity in Humans

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different “genetic signatures” of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity

Relapse prevention for addictive behaviors

The Relapse Prevention (RP) model has been a mainstay of addictions theory and treatment since its introduction three decades ago. This paper provides an overview and update of RP for addictive behaviors with a focus on developments over the last decade (2000-2010). Major treatment outcome studies and meta-analyses are summarized, as are selected empirical findings relevant to the tenets of the RP model. Notable advances in RP in the last decade include the introduction of a reformulated cognitive-behavioral model of relapse, the application of advanced statistical methods to model relapse in large randomized trials, and the development of mindfulness-based relapse prevention. We also review the emergent literature on genetic correlates of relapse following pharmacological and behavioral treatments. The continued influence of RP is evidenced by its integration in most cognitive-behavioral substance use interventions. However, the tendency to subsume RP within other treatment modalities has posed a barrier to systematic evaluation of the RP model. Overall, RP remains an influential cognitive-behavioral framework that can inform both theoretical and clinical approaches to understanding and facilitating behavior change

Nitrous Oxide Inhalation Among Adolescents: Prevalence, Correlates, and Co-Occurrence with Volatile Solvent Inhalation

Few studies have examined the prevalence of nitrous oxide (NO) inhalation or co-occurrence of NO and volatile solvent (VS) use in adolescents. Study aims were to (1) describe the independent and conjoint prevalence of NO and VS use in incarcerated youth, (2) compare adolescent users of both NO and VS inhalants (NO+VS) to users of NO-only, VS-only, and nonusers of NO and VS (NO/VNS nonusers) with regard to demographic, psychological, and behavioral characteristics, and (3) conduct logistic regression analyses identifying correlates of NO use. Residents (N = 723) of Missouri Division of Youth Services were assessed with standardized psychosocial measures. Participants averaged 15.5 (SD = 1.2) years of age, were ethnically diverse and predominantly male. Lifetime prevalence of NO use was 15.8%. NO+VS users evidenced greater impairments compared to NO+VS nonusers. VS-only users evidenced impairments that were similar in kind but at lower prevalences compared to those displayed by NO+VS users, whereas NO-only youth had profiles that were similar to those of NO/VS nonusers. Psychiatric disorders, polydrug use, and temperamental fearlessness were correlates of NO use. NO+VS users were at high risk for behavioral and emotional problems. Screening and interventions for NO and VS inhalant use should be implemented in juvenile justice facilities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78160/1/nihms217666.pd

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe