Quantum-spacetime scenarios and soft spectral lags of the remarkable GRB130427A

We process the Fermi LAT data on GRB130427A using the Fermi Science Tools, and we summarize some of the key facts that render this observation truly remarkable, especially concerning the quality of information on high-energy emission by GRBs. We then exploit this richness for a search of spectral lags, of the type that has been recently of interest for its relevance in quantum-spacetime research. We do find some evidence of systematic soft spectral lags: when confining the analysis to photons of energies greater than 5 GeV there is an early hard development of minibursts within this long burst. The effect turns out to be well characterized quantitatively by a linear dependence, within such a miniburst, of the detection time on energy. With the guidance of our findings for GRB130427A we can then recognize that some support for these features is noticeable also in earlier Fermi-LAT GRBs, particularly for the presence of hard minibursts whose onset is marked by the highest-energy photon observed for the GRB. A comparison of these features for GRBs at different redshifts provides some encouragement for a redshift dependence of the effects of the type expected for a quantum-spacetime interpretation, but other aspects of the analysis appear to invite the interpretation as intrinsic properties of GRBs

Demography of high redshift AGN

High redshift AGN holds the key to understand the early structure formation and to probe the Universe during its infancy. We review the latest searches for high-z AGN in the deepest X-ray field so far, the Chandra Deep Field South (CDFS) 4 Msecond exposure. We do not confirm the positive detection of a signal in the stacked Chandra images at the position of z~6 galaxies recently reported by Treister and collaborators. We present z>3 X-ray sources number counts in the 0.5-2 keV band obtained joining CDFS faint detections with Chandra-COSMOS and XMM-COSMOS detections. We use these number counts to make predictions for surveys with three mission concepts: Athena, WFXT and a Super-Chandra.Comment: Advances in Astronomy Special Issue "Seeking for the Leading Actor on the Cosmic Stage: Galaxies versus Supermassive Black Holes

A Comparison of Marketing Techniques Among Military Recruiters

The U.S. Department of Defense spent $11 billion in enlistment and retention bonuses from 2006 to 2010, which had only a marginally positive effect on the enlistment rate for the Army. The case study addressed this business problem of recruiting by exploring marketing strategies successful recruiting professionals used to motivate individuals to join the military. The purpose of this study was to determine effective recruiting strategies. Therefore, it incorporated the conceptual framework of emergent strategy theory, which postulated the best strategies are neither completely planned nor completely random, but are rather an adaptation to changing dynamics and circumstances. The population consisted of 2 former recruiters, 1 from the Army and another from the Marine Corps, as well as 38 college students located in Wilkes-Barre, Pennsylvania. Data for the study morphed from face-to-face interviews and 3 focus groups comprised of 10 to 15 students each, for the purpose of addressing the research question. Data analysis occurred through a process of coding and theming. The 9 themes identified included tell the story, advertising strategies, and fit for duty. A lesson learned from these themes was that the key for successful recruiting strategies lies in aligning with the wants and needs of individuals in the target demographic. If senior leaders in the Department of Defense followed the recommendations provided, each of the branches of the military service could potentially achieve higher recruiting rates at a lower cost. The study could result in social change whereby eligible recruits could view the Army and Marine Corps as professions of arms in which individuals can live out their ideals of patriotism but also have a good quality of life due to the benefits of military service

Erratum: Lipase-catalyzed regioselective acylation of resorcin[4]arenes (Journal of Molecular Catalysis B: Enzymatic (2002) 16 (24-247) PII: S1381117701000686)

10Immobilized lipase from Mucor miehei (RML) catalyzed the regioselective acylation of the C-2 side-chain of the C-alkyl resorcin[4]arene tetra-alcohol 1 in the 1,2-alternate form in organic solvents using vinyl acetate as acylating reagent. The influence of reaction parameters and solvent choice were also studied. Docking simulations allowed the determination of the binding geometry of 1, revealing the importance of Trp88 residue in stabilizing the Michaelis–Menten complex between enzyme and substrate.reservedmixedBotta, Bruno; Zappia, Giovanni; Tafi, Andrea; Botta, Maurizio; Manetti, Fabrizio; Cernia, Enrico; Milana, Giuliana; Palocci, Cleofe; Soro, Simonetta; Delle Monache, GiulianoBotta, Bruno; Zappia, Giovanni; Tafi, Andrea; Botta, Maurizio; Manetti, Fabrizio; Cernia, Enrico; Milana, Giuliana; Palocci, Cleofe; Soro, Simonetta; Delle Monache, Giulian

High-density lipoprotein contribute to G0-G1/S transition in Swiss NIH/3T3 fibroblasts

High density lipoproteins (HDLs) play a crucial role in removing excess cholesterol from peripheral tissues. Although their concentration is lower during conditions of high cell growth rate (cancer and infections), their involvement during cell proliferation is not known. To this aim, we investigated the replicative cycles in synchronized Swiss 3T3 fibroblasts in different experimental conditions: i) contact-inhibited fibroblasts re-entering cell cycle after dilution; ii) scratch-wound assay; iii) serum deprived cells induced to re-enter G1 by FCS, HDL or PDGF. Analyses were performed during each cell cycle up to quiescence. Cholesterol synthesis increased remarkably during the replicative cycles, decreasing only after cells reached confluence. In contrast, cholesteryl ester (CE) synthesis and content were high at 24h after dilution and then decreased steeply in the successive cycles. Flow cytometry analysis of DiO-HDL, as well as radiolabeled HDL pulse, demonstrated a significant uptake of CE-HDL in 24h. DiI-HDL uptake, lipid droplets (LDs) and SR-BI immunostaining and expression followed the same trend. Addition of HDL or PDGF partially restore the proliferation rate and significantly increase SR-BI and pAKT expression in serum-deprived cells. In conclusion, cell transition from G0 to G1/S requires CE-HDL uptake, leading to CE-HDL/SR-BI pathway activation and CEs increase into LDs

Content, mineral allocation and leaching behavior of heavy metals in urban PM2.5

This work provides a novel perspective in the field of urban airborne particle investigation that is not currently found in the literature. Four sampling campaigns were performed in the urban area of Rome (Central Italy) during the winter and summer seasons (February and July 2013 and 2014, respectively). The measured concentrations of the regulated 34 elements of As, Cd, Ni and Pb were consistent with those reported by the local Environmental Agency (ARPA Lazio), but non-regulated heavy metals, including Fe, Cu, Cr and Zn, were also found in PM2.5 and analyzed in detail. As an novelty, heavy metals were associated with the host-identified mineral phases, primarily oxides and alloys, and to a lesser extent, other minerals, such as sulfates, carbonates and silicates. Leaching tests of the collected samples were conducted in a buffered solution mimicking the bodily physiological environment. Despite the highest concentration of heavy metals found during the winter sampling period, all of the elements showed a leaching trend leading to major mobility during the summer period. To explain this result, an interesting comparative analysis between the leaching test behavior and innovative mineral allocation was conducted. Both the heavy metal content and mineral allocation in PM2.5 might contribute to the bioavailability of toxic elements in the pulmonary environment. Hence, for regulatory purposes, the non-linear dependency of heavy metal bioavailability on the total metal content should be taken into account

Treg/Tcon Immunotherapy and High Dose Marrow Irradiation Ensure Full Control of Leukemia Relapse in Haploidentical Transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most powerful therapy for patients with high risk of relapse. In spite of that, no matter the donor source or conditioning regimen used, leukemia relapse is still the leading cause of HSCT failure. In HLA-haploidentical HSCT, we recently applied a clinical protocol consisting of total body irradiation (TBI)-based conditioning regimen and a peripheral blood CD34+ cell graft combined with the adoptive transfer of naturally occurring regulatory T cells (Tregs) and conventional T cells (Tcons). No post-transplant pharmacologic GvHD prophylaxis was given. Such protocol was associated with low GvHD and relapse rate (Martelli et al., Blood 2014). To further reduce leukemia relapse in Treg/Tcon-based haploidentical HSCT (Treg/Tcon haplo-HSCT) we used high dose hyper-fractionated TBI (HF-TBI) in the conditioning regimen. We also extended Treg/Tcon haplo-HSCT to patients that are unfit (because of previous comorbidities) and/or too old to withstand high intensity regimens. In these patients the extra-hematologic toxicity of irradiation was reduced with the use of targeted total marrow and lymph node irradiation (TMLI). 40 patients with high risk acute leukemia (36 AML, 4 ALL) received Treg/Tcon haplo-HSCT. All but 3 patients were transplanted in complete remission. 12 younger patients (median age: 28, range: 20-43) received HF-TBI, while 28 older or unfit patients (59, 40-70) received TMLI in the conditioning regimen. HF-TBI (14.4 Gy) was administered in 12 fractions, 3 times a day for 4 days. TMLI was administered by means of Helical Tomotherapy HI-ART (9 fractions, 2 times a day for 4.5 days). Irradiation was followed by chemotherapy with Thiotepa, Fludarabine, and Cyclophosphamide. 2 × 106/kg freshly isolated CD4+CD25+FOXP3+ Tregs were transferred 4 days before the infusion of 1 × 106/kg Tcons and a mega-dose of CD34+ hematopoietic stem cells. No post-transplant pharmacologic GvHD prophylaxis was given. 38/40 patients engrafted. 12 (31%) developed aGvHD grade ³2 (10 are alive and off-therapy). 6 (16%) died because of transplant related complications (2 because of aGvHD, 2 infections, 1 veno-occlusive disease, 1 intracranial hemorrhage). Strikingly, despite the high risk diseases, no patient relapsed after a median follow up of 13 months (range 1-36, Fig. A). Further, only 1 patient developed cGvHD. Thus, cGvHD/Leukemia-free survival was 82% (Fig. B). Treg adoptive transfer allows for the safe infusion of an otherwise lethal dose of donor alloreactive Tcons in the absence of any other form of immune suppression. Our results demonstrate that the potent graft versus leukemia effect of Treg/Tcon adoptive transfer was boosted by high dose marrow irradiation. Thus, this study proves that the right combination of haploidentical Treg/Tcon immunotherapy plus a powerful conditioning regimen can fully eradicate leukemia

MK-4101 - a potent inhibitor of the hedgehog pathway - is highly active against medulloblastoma and basal cell carcinoma

Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/- mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for treatment of medulloblastoma and BCC. Results clearly demonstrated a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/- mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidated the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in tumor cells, showing the maximum inhibitory effect on Gli1. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways, were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity