Anisotropy and chemical composition of ultra-high energy cosmic rays using arrival directions measured by the Pierre Auger Observatory

The Pierre Auger Collaboration has reported evidence for anisotropy in the distribution of arrival directions of the cosmic rays with energies $E>E_{th}=5.5\times 10^{19}$ eV. These show a correlation with the distribution of nearby extragalactic objects, including an apparent excess around the direction of Centaurus A. If the particles responsible for these excesses at $E>E_{th}$ are heavy nuclei with charge $Z$, the proton component of the sources should lead to excesses in the same regions at energies $E/Z$. We here report the lack of anisotropies in these directions at energies above $E_{th}/Z$ (for illustrative values of $Z=6,\ 13,\ 26$). If the anisotropies above $E_{th}$ are due to nuclei with charge $Z$, and under reasonable assumptions about the acceleration process, these observations imply stringent constraints on the allowed proton fraction at the lower energies

Advanced functionality for radio analysis in the Offline software framework of the Pierre Auger Observatory

The advent of the Auger Engineering Radio Array (AERA) necessitates the development of a powerful framework for the analysis of radio measurements of cosmic ray air showers. As AERA performs "radio-hybrid" measurements of air shower radio emission in coincidence with the surface particle detectors and fluorescence telescopes of the Pierre Auger Observatory, the radio analysis functionality had to be incorporated in the existing hybrid analysis solutions for fluoresence and surface detector data. This goal has been achieved in a natural way by extending the existing Auger Offline software framework with radio functionality. In this article, we lay out the design, highlights and features of the radio extension implemented in the Auger Offline framework. Its functionality has achieved a high degree of sophistication and offers advanced features such as vectorial reconstruction of the electric field, advanced signal processing algorithms, a transparent and efficient handling of FFTs, a very detailed simulation of detector effects, and the read-in of multiple data formats including data from various radio simulation codes. The source code of this radio functionality can be made available to interested parties on request.Comment: accepted for publication in NIM A, 13 pages, minor corrections to author list and references in v

Search for First Harmonic Modulation in the Right Ascension Distribution of Cosmic Rays Detected at the Pierre Auger Observatory

We present the results of searches for dipolar-type anisotropies in different energy ranges above $2.5\times 10^{17}$ eV with the surface detector array of the Pierre Auger Observatory, reporting on both the phase and the amplitude measurements of the first harmonic modulation in the right-ascension distribution. Upper limits on the amplitudes are obtained, which provide the most stringent bounds at present, being below 2% at 99% $C.L.$ for EeV energies. We also compare our results to those of previous experiments as well as with some theoretical expectations.Comment: 28 pages, 11 figure

Clinical isolates of the modern Mycobacterium tuberculosis lineage 4 evade host defense in human macrophages through eluding IL-1\u3b2-induced autophagy article

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), has infected over 1.7 billion people worldwide and causes 1.4 million deaths annually. Recently, genome sequence analysis has allowed the reconstruction of Mycobacterium tuberculosis complex (MTBC) evolution, with the identification of seven phylogeographic lineages: four referred to as evolutionarily "ancient", and three "modern". The MTBC strains belonging to "modern" lineages appear to show enhanced virulence that may have warranted improved transmission in humans over ancient lineages through molecular mechanisms that remain to be fully characterized. To evaluate the impact of MTBC genetic diversity on the innate immune response, we analyzed intracellular bacterial replication, inflammatory cytokine levels, and autophagy response in human primary macrophages infected with MTBC clinical isolates belonging to the ancient lineages 1 and 5, and the modern lineage 4. We show that, when compared to ancient lineage 1 and 5, MTBC strains belonging to modern lineage 4 show a higher rate of replication, associated to a significant production of proinflammatory cytokines (IL-1\u3b2, IL-6, and TNF-\u3b1) and induction of a functional autophagy process. Interestingly, we found that the increased autophagic flux observed in macrophages infected with modern MTBC is due to an autocrine activity of the proinflammatory cytokine IL-1\u3b2, since autophagosome maturation is blocked by an interleukin-1 receptor antagonist. Unexpectedly, IL-1\u3b2-induced autophagy is not disadvantageous for the survival of modern Mtb strains, which reside within Rab5-positive phagosomal vesicles and avoid autophagosome engulfment. Altogether, these results suggest that autophagy triggered by inflammatory cytokines is compatible with a high rate of intracellular bacilli replication and may therefore contribute to the increased pathogenicity of the modern MTBC lineages

Private information arrival, trading activity, and price formation: Evidence from nonpublic merger negotiations

Abstract: We provide evidence on how stock prices and trading activity respond to the arrival of private information about firm value using the dates of material nonpublic merger negotiations to proxy for private information arrival. Target firm returns are 0.41% higher over two days following each nonpublic negotiation event. Trading volume, order imbalance, and trade size also spike in this window. Larger price reactions following negotiation events preempt deal announcement returns. The price response following negotiation events is explained by proxies for the expected profits and price impact of informed trading, prior press speculation, institutional ownership, and contemporaneous trading activity signals. We thank Linda Bamber, Diane Del Guercio, Ro Gutierrez, Kathy Kahle, Ron Kaniel, Eric Kelley, Chris Lamoureux, Jochen Lawrenz, Lubo Litov, Wayne Mikkelson, Bill Schwert, Rick Sias, Jerry Warner, and workshop participants at MIT, and the Universities of Arizona, Georgia, Innsbruck, Oregon, Rochester, and Utah for helpful comments. We are also grateful to Denis Sosyura (discussant) and participants at the 2012 University of Washington Summer Finance Conference. We recognize the excellent research assistance provided by Tyler Brough, Michael Dambra, Douglas Fairhurst, Jordan Neyland, and Matthew Serfling. * Rochester, NY 14627; phone: 585.273.4818; email: [email protected] ** Tucson, AZ 85721; phone: 520.621.8761; email: [email protected] 1 Understanding the degree to which investors rapidly acquire and trade on new private information about firm value and how their trades affect price formation is central to the design of securities regulation and inferences about the efficiency of financial markets. The evidence in a number of recent studies shows that informed investors obtain private information in a variety of ways, such as through connections to insiders, and that they use this information to make profitable trades. For instance, To infer private information-based trades, the aforementioned studies often begin with a firm's disclosure of earnings or the announcement of a merger agreement and examine trading behavior and price movements over a brief window before the disclosure. But, ascertaining whether connected investors trade on private information is challenging in part due to the difficulty of tying stock returns and trading decisions to the underlying arrival of private information. Because securities regulation does not generally compel managers to disclose material nonpublic information immediately, traders can acquire and exploit private information weeks or months before the firm is required to disclose it. In this paper we study underlying events that produce and distribute private information about the value of a firm. Specifically, we use the dates of merger negotiations that occur privately, but are disclosed weeks or months after the deal is announced, to more precisely identify when private information is actually generated. These data allow us to examine whether informed investors promptly trade on private information that arrives during the course of merger 2 negotiations and if their trading has an economically important effect on target firms' stock prices. 1 For a sample of 545 completed acquisitions announced between 1995 and 2006, we use Securities and Exchange Commission (SEC)-mandated background disclosures to identify the dates and types of various material "events" that occur during negotiations between the target and potential acquirers before an acquisition deal is announced. These nonpublic negotiation events include, for example, the initiation of merger talks, a bidder making a private offer for the target, the retention of a financial advisor, or a meeting of the target's board to evaluate a proposed deal. On average, over the three months prior to the merging parties' disclosure of a preliminary merger agreement (hereafter, referred to as the deal announcement), there are about seven unique trading days during which at least one material negotiation event occurs. After controlling for the impact of press speculation about a potential acquisition deal (which affects 18% of the deals in our sample) we find that for each nonpublic negotiation event, target firm excess abnormal returns average 0.18% the same day and 0.23% the day after the event, resulting in a two-day estimated excess return of 0.41%. These returns are incremental to the average positive abnormal returns during the negotiation period and thus provide a lower-bound estimate of the price impact of trading on private information about merger negotiations. To more fully understand the source of these returns, we examine whether non-price measures of informed trading are also related to the arrival of private information during merger negotiations. We document significant spikes in abnormal trading volume, buyer-initiated transactions measured by order imbalance, and medium-size trades over the two-day window following a nonpublic negotiation event. Moreover, we also find that increases in contemporaneous 1 Informed trading before a merger announcement includes both illegal insider trading on material nonpublic information and legitimate trading based on superior information acquisition and processing. Moreover, the term "insider" in insider trading as used in this paper refers to any individual that knowingly trades on material nonpublic information. This could include, but is not limited to, corporate insiders as defined under Section 16 requirements for reporting trades (e.g., officers, directors, and some blockholders). See Agrawal and Jaffe (1995) and Agrawal and Nasser (2012) for evidence on trading by corporate insiders prior to merger announcements. 3 volume, buy-sell order imbalance, and medium-size trades predict stock returns following negotiation events. For example, a ten percentage point increase in abnormal trading volume is associated with a 12 basis point larger stock price reaction to each negotiation event. These effects are incremental to the typical effect of trading activity on stock returns and suggest that the arrival of private information about merger negotiations has substantive implications for understanding the trading decisions of informed investors and the informational efficiency of stock prices. Next, we investigate whether firm and deal-specific factors explain how quickly target stock prices respond to the arrival of private information. We show that stock returns following negotiation events are increasing in both the expected profits from trading on private information, as measured by the offer premium, and the likelihood of deal completion, captured by a tender offer or target termination fee clause. We further document that the magnitude of the stock price response is increasing in the adverse selection costs of trading in the target firm's shares, proxied by PIN (probability of informed trading) and low analyst coverage. In other words, stock returns are more sensitive to negotiation events for firms whose stock price is generally more sensitive to informed trades. We also find that higher institutional ownership is associated with a decrease in the sensitivity of stock returns to negotiation events. This evidence suggests that institutions may be less willing than individuals to trade on private information from negotiation events or that if they do trade on this information, they do not do so immediately after a negotiation event. We also examine whether media speculation about a deal is related to the sensitivity of target firm stock returns to nonpublic negotiation events. Controlling for the market's reaction to a rumor, we show that for the 18% of the deals in our sample with at least one published rumor prior to the deal announcement, the target firm's stock returns respond significantly more to negotiation events. Further, we document that this effect is most pronounced for nonpublic negotiation events that occur after the rumor is published. These findings are consistent with the conventional wisdom that 4 the litigation risk from trading on private information is decreasing in the amount of existing public information about a potential deal and with the notion that because press speculation increases target firms' stock return volatility, news rumors make it easier for informed investors to trade without detection from other traders. We investigate the factors that determine the timing and occurrence of press speculation. Indicating that private information from merger negotiations is in some instances quickly leaked to the media, we show that although press rumors tend to follow observable abnormal stock returns and trading volume, they are incrementally more likely to take place over the two days following a nonpublic negotiation event. Further, implying that informed investors are potentially responsible for at least some of this leakage, we find that a deal is more likely to be rumored when the set of investors with private information about deal negotiations is larger, proxied for with measures for the number of deal insiders (Acharya and Johnson One interpretation of this finding is that, at times, informed investors intentionally leak some of their private information to the press so they can more easily trade on the remainder of their information. To further assess the economic importance of informed trading following the arrival of private information, we examine the extent to which the price impact of this trading affects the target's acquisition price and the market's reaction to the announcement of a merger agreement. Schwert's (1996) evidence suggests that for every 1 increase in the target's stock price prior to the deal announcement, the target negotiates more than a 1 increase in the final acquisition price from the acquirer. However, acquirers and targets know the dates they negotiated, and thus, acquirers should be able to discount stock price movements occurring just after negotiation events. Our results suggest that a $1 increase in stock price attributable to informed trading following nonpublic negotiation events leads to a$0.81 increase in the final transaction price, a significant 29% discount from the $1.14 increase in the final transaction price for each$1 of non-event price increase. In 5 other words, deal negotiators place a lower weight on stock returns linked to nonpublic negotiation event days than stock returns on other days. We also find that a one percent increase in the target's stock price attributable to informed trading following nonpublic negotiation events reduces the market's reaction to the deal announcement by 26 basis points. However, a similar one percent increase in stock price during the period prior to the deal announcement that is not attributable to negotiation events reduces the market's reaction by only 13 basis points. These findings imply that private information-based trading following merger negotiations is economically important in preempting the information in the deal announcement. Our study contributes to the literature that considers how public and private information impacts trading decisions and price formation. We use a novel but intuitive approach to provide insights on private information-based trading and its impact on price formation by focusing on the dates when private information is created. Our evidence indicates that well-informed traders rapidly exploit their information advantage. Their trades are reflected in volume, order flow, and trade size, and have an economically important effect on a firm's stock price. Further, we identify several factors that determine the magnitude of the stock price reaction to the arrival of private information during merger negotiations. The stock price reaction depends on contemporaneous volume and order flow, expected profits from trading on private information, the expected price impact of informed trading, institutional ownership, and whether a private negotiation event is preceded by press speculation. Implying that informed trading following merger negotiations preempts information in the deal announcement, we also show that stock returns linked to days with private information events are associated with significantly smaller deal announcement returns. This study also contributes to the emerging literature on how traders' characteristics and connections to insiders impact the timing and profitability of their trades and the efficiency of stock 6 prices. Our focus on days when information is produced and distributed provides an avenue for future research to examine how the trades of specific investors correlate with the arrival of private information. Given that we document trading activity and stock returns respond quickly to the arrival of new private information about firm value, our evidence also speaks to the SEC's focus on hedge funds, brokerages, deal advisers, and exchange traders and their access to and use of confidential inside information. The remainder of the paper is organized as follows. Section 1 reviews prior work on private information-based trading and discusses the potential for such trading activity subsequent to merger negotiations. Section 2 presents our empirical results. Section 3 concludes. Informed Trading and the Timing of Nonpublic Merger Negotiations Asymmetric information is a pervasive trait of capital markets. The intent of disclosure regulation is to ensure that material information is disclosed to investors, but there are few mandatory obligations for real-time disclosure of new information. As a result, stock prices can diverge from their full information value. Public disclosure of material nonpublic information may be delayed for weeks or even months, thereby providing incentives for traders to uncover private information. Traders with more precise information about a firm's value are more likely to trade on their information. In the absence of public disclosure of new information, the speed at which price converges to its full information value depends on informed trading. Profit-maximizing informed traders have incentives to camouflage their trades by spreading them out over time As the number of privately-informed investors grows, competition between them can create incentives to trade more aggressively, leading to more efficient prices (Holden and Subrahmanyam 7 (1992)). In contrast, 2 We focus on the timing of nonpublic merger negotiations to identify informed trading activity and its effect on price formation. 3 An informed investor's trading incentives depend on how negotiations progress, the expected offer price relative to the current price (the premium), and the likelihood of a successful deal. The distribution of that private information during negotiations also matters. The initial contact between the merging parties is often between CEOs and a few close advisors and directors. As discussions progress, the target's (and often the acquirer's) entire board is informed, financial and legal advisors are retained, investment bankers are contacted to assist with financing, and lower-level managers and auditors are brought in to support the due diligence process and integration planning. While the negotiating managers, directors, advisors, and financing 2 Prior studies that attempt to link trading on private information prior to acquisitions with target stock price formation look at the magnitude of stock price runups in acquisition targets 5 4 Expert networks are one of the interesting targets of recent insider trading investigations. Expert networks retain current and past managers and other industry specialists as consultants to investors such as mutual funds and hedge funds. While expert network firms have policies that bar their consultants from passing along confidential information, it appears that many consultants have done so. A recent complaint filed by the SEC alleges that ten consultants and one investment advisor working for the expert network firm Primary Global Research (PGR) passed along material nonpublic information to hedge funds and other PGR clients in exchange for cash compensation. The SEC alleges that the clients of PGR earned about $30 million in illicit profits as a result (SEC vs. Longria et a

Mycobacterium marinum antagonistically induces an autophagic response while repressing the autophagic flux in a TORC1- and ESX-1-dependent manner.

Autophagy is a eukaryotic catabolic process also participating in cell-autonomous defence. Infected host cells generate double-membrane autophagosomes that mature in autolysosomes to engulf, kill and digest cytoplasmic pathogens. However, several bacteria subvert autophagy and benefit from its machinery and functions. Monitoring infection stages by genetics, pharmacology and microscopy, we demonstrate that the ESX-1 secretion system of Mycobacterium marinum, a close relative to M. tuberculosis, upregulates the transcription of autophagy genes, and stimulates autophagosome formation and recruitment to the mycobacteria-containing vacuole (MCV) in the host model organism Dictyostelium. Antagonistically, ESX-1 is also essential to block the autophagic flux and deplete the MCV of proteolytic activity. Activators of the TORC1 complex localize to the MCV in an ESX-1-dependent manner, suggesting an important role in the manipulation of autophagy by mycobacteria. Our findings suggest that the infection by M. marinum activates an autophagic response that is simultaneously repressed and exploited by the bacterium to support its survival inside the MCV

Deficiency in the autophagy modulator Dram1 exacerbates pyroptotic cell death of Mycobacteria-infected macrophages

DNA damage regulated autophagy modulator 1 (DRAM1) is a stress-inducible regulator of autophagy and cell death. DRAM1 has been implicated in cancer, myocardial infarction, and infectious diseases, but the molecular and cellular functions of this transmembrane protein remain poorly understood. Previously, we have proposed DRAM1 as a host resistance factor for tuberculosis (TB) and a potential target for host-directed anti-infective therapies. In this study, we generated a zebrafish dram1 mutant and investigated its loss-of-function effects during Mycobacterium marinum (Mm) infection, a widely used model in TB research. In agreement with previous knockdown analysis, dram1 mutation increased the susceptibility of zebrafish larvae to Mm infection. RNA sequencing revealed major effects of Dram1 deficiency on metabolic, immune response, and cell death pathways during Mm infection, and only minor effects on proteinase and metabolic pathways were found under uninfected conditions. Furthermore, unchallenged dram1 mutants did not display overt autophagic defects, but autophagic targeting of Mm was reduced in the absence of Dram1. The phagocytic ability of macrophages in dram1 mutants was unaffected, but acidification of Mm-containing vesicles was strongly reduced, indicating that Dram1 is required for phagosome maturation. By in vivo imaging, we observed that Dram1-deficient macrophages fail to restrict Mm during early stages of infection. The resulting increase in bacterial burden could be reverted by knockdown of inflammatory caspase a (caspa) and gasdermin Eb (gsdmeb), demonstrating pyroptosis as the mechanism underlying premature cell death of Mm-infected macrophages in dram1 mutants. Collectively, these data demonstrate that dissemination of mycobacterial infection in zebrafish larvae is promoted in the absence of Dram1 due to reduced maturation of mycobacteria-containing vesicles, failed intracellular containment, and consequent pyroptotic death of infected macrophages. These results provide new evidence that Dram1 plays a central role in host resistance to intracellular infection, acting at the crossroad of autophagy and cell death

A Role for the Retinoblastoma Protein As a Regulator of Mouse Osteoblast Cell Adhesion: Implications for Osteogenesis and Osteosarcoma Formation

The retinoblastoma protein (pRb) is a cell cycle regulator inactivated in most human cancers. Loss of pRb function results from mutations in the gene coding for pRb or for any of its upstream regulators. Although pRb is predominantly known as a cell cycle repressor, our data point to additional pRb functions in cell adhesion. Our data show that pRb regulates the expression of a wide repertoire of cell adhesion genes and regulates the assembly of the adherens junctions required for cell adhesion. We conducted our studies in osteoblasts, which depend on both pRb and on cell-to-cell contacts for their differentiation and function. We generated knockout mice in which the RB gene was excised specifically in osteoblasts using the cre-lox P system and found that osteoblasts from pRb knockout mice did not assemble adherens junction at their membranes. pRb depletion in wild type osteoblasts using RNAi also disrupted adherens junctions. Microarrays comparing pRb-expressing and pRb-deficient osteoblasts showed that pRb controls the expression of a number of cell adhesion genes, including cadherins. Furthermore, pRb knockout mice showed bone abnormalities consistent with osteoblast adhesion defects. We also found that pRb controls the function of merlin, a well-known regulator of adherens junction assembly, by repressing Rac1 and its effector Pak1. Using qRT-PCR, immunoblots, co-immunoprecipitation assays, and immunofluorescent labeling, we observed that pRb loss resulted in Rac1 and Pak1 overexpression concomitant with merlin inactivation by Pak1, merlin detachment from the membrane, and adherens junction loss. Our data support a pRb function in cell adhesion while elucidating the mechanism for this function. Our work suggests that in some tumor types pRb inactivation results in both a loss of cell cycle control that promotes initial tumor growth as well as in a loss of cell-to-cell contacts, which contributes to later stages of metastasis

Understory Bird Communities in Amazonian Rainforest Fragments: Species Turnover through 25 Years Post-Isolation in Recovering Landscapes

Inferences about species loss following habitat conversion are typically drawn from short-term surveys, which cannot reconstruct long-term temporal dynamics of extinction and colonization. A long-term view can be critical, however, to determine the stability of communities within fragments. Likewise, landscape dynamics must be considered, as second growth structure and overall forest cover contribute to processes in fragments. Here we examine bird communities in 11 Amazonian rainforest fragments of 1–100 ha, beginning before the fragments were isolated in the 1980s, and continuing through 2007. Using a method that accounts for imperfect detection, we estimated extinction and colonization based on standardized mist-net surveys within discreet time intervals (1–2 preisolation samples and 4–5 post-isolation samples). Between preisolation and 2007, all fragments lost species in an area-dependent fashion, with loss of as few as <10% of preisolation species from 100-ha fragments, but up to 70% in 1-ha fragments. Analysis of individual time intervals revealed that the 2007 result was not due to gradual species loss beginning at isolation; both extinction and colonization occurred in every time interval. In the last two samples, 2000 and 2007, extinction and colonization were approximately balanced. Further, 97 of 101 species netted before isolation were detected in at least one fragment in 2007. Although a small subset of species is extremely vulnerable to fragmentation, and predictably goes extinct in fragments, developing second growth in the matrix around fragments encourages recolonization in our landscapes. Species richness in these fragments now reflects local turnover, not long-term attrition of species. We expect that similar processes could be operating in other fragmented systems that show unexpectedly low extinction

Analytical methods applied to diverse types of Brazilian propolis

Propolis is a bee product, composed mainly of plant resins and beeswax, therefore its chemical composition varies due to the geographic and plant origins of these resins, as well as the species of bee. Brazil is an important supplier of propolis on the world market and, although green colored propolis from the southeast is the most known and studied, several other types of propolis from Apis mellifera and native stingless bees (also called cerumen) can be found. Propolis is usually consumed as an extract, so the type of solvent and extractive procedures employed further affect its composition. Methods used for the extraction; analysis the percentage of resins, wax and insoluble material in crude propolis; determination of phenolic, flavonoid, amino acid and heavy metal contents are reviewed herein. Different chromatographic methods applied to the separation, identification and quantification of Brazilian propolis components and their relative strengths are discussed; as well as direct insertion mass spectrometry fingerprinting