The Fermi Bubble as a Source of Cosmic Rays in the Energy Range > 10E15 eV

The {\it Fermi} Large Area Telescope has recently discovered two giant gamma-ray bubbles which extend north and south of the Galactic center with diameters and heights of the order of $H\sim 10$ kpc. We suggest that the periodic star capture processes by the Galactic supermassive black hole Sgr A$^*$, with a capture rate of $\tau_{\rm cap}^{-1}\sim 3\times 10^{-5}$ yr$^{-1}$ and an energy release of $W\sim 3\times 10^{52}$ erg per capture, can result in hot plasma injecting into the Galactic halo at a wind velocity of $u\sim 10^8$ cm s$^{-1}$. The periodic injection of hot plasma can produce a series of shocks. Energetic protons in the bubble are re-accelerated when they interact with these shocks. We show that for energy larger than $E> 10^{15}$ eV, the acceleration process can be better described by the stochastic second-order Fermi acceleration. We propose that hadronic cosmic rays (CRs) within the ``knee'' of the observed CR spectrum are produced by Galactic supernova remnants distributed in the Galactic disk. Re-acceleration of these particles in the Fermi Bubble produces CRs beyond the knee. With a mean CR diffusion coefficient in this energy range in the bubble $D_B\sim 3\times 10^{30}$ cm$^2$ s$^{-1}$, we can reproduce the spectral index of the spectrum beyond the knee and within. The conversion efficiency from shock energy of the bubble into CR energy is about 10\%. This model provides a natural explanation of the observed CR flux, spectral indices, and matching of spectra at the knee.Comment: 43 pages, 8 figues, to be published in the Astrophysical Journal; version 2, 45 pages, 8 figures, added references and corrected typo

Efficacy of a Solution Composed by Verbascoside, Polyvinylpyrrolidone (PVP) and Sodium Hyaluronate in the Treatment of Chemotherapy-induced Oral Mucositis in Children With Acute Lymphoblastic Leukemia

Summary: The aim of this study was to assess the efficacy of a solution composed by verbascoside, polyvinylpyrrolidone, and sodium hyaluronate (Mucosyte) in the treatment of chemotherapy- induced oral mucositi (OM). Patients between 5 and 18 years receiving chemotherapy for acute lymphoblastic leukemia and with OM grade 1 or 2 were randomized in group A (treated with Mucosyte, 3 mouthwashes/d per 8d) and group B (treated with placebo, ie, an inert water-based solution, 3 mouthwashes/d per 8 d). The OM scoring was performed at day 1 (diagnosis of OM- T0), after 3 days of treatment (T1), and at day 8 (T2). Pain was evaluated through the visual analog scale with the same timing of OM measurement. A total of 56 patients were included (28 patients per group). Group A experienced a statistically significant decline of OM at T2 (P=0.0038); a statistically significant difference in pain reduction between 2 groups both at T1 and at T2 (P < 0.005) was observed. The use of Mucosyte mouthwashes in children with chemotherapy-induced OM may be recommended as supportive therapy

Small RNA analysis in Sindbis virus infected human HEK293 cells

In contrast to the defence mechanism of RNA interference (RNAi) in plants and invertebrates, its role in the innate response to virus infection of mammals is a matter of debate. Since RNAi has a well-established role in controlling infection of the alphavirus Sindbis virus (SINV) in insects, we have used this virus to investigate the role of RNAi in SINV infection of human cells

Experimental Evolution of an Oncolytic Vesicular Stomatitis Virus with Increased Selectivity for p53-Deficient Cells

Experimental evolution has been used for various biotechnological applications including protein and microbial cell engineering, but less commonly in the field of oncolytic virotherapy. Here, we sought to adapt a rapidly evolving RNA virus to cells deficient for the tumor suppressor gene p53, a hallmark of cancer cells. To achieve this goal, we established four independent evolution lines of the vesicular stomatitis virus (VSV) in p53-knockout mouse embryonic fibroblasts (p53−/− MEFs) under conditions favoring the action of natural selection. We found that some evolved viruses showed increased fitness and cytotoxicity in p53−/− cells but not in isogenic p53+/+ cells, indicating gene-specific adaptation. However, full-length sequencing revealed no obvious or previously described genetic changes associated with oncolytic activity. Half-maximal effective dose (EC50) assays in mouse p53-positive colon cancer (CT26) and p53-deficient breast cancer (4T1) cells indicated that the evolved viruses were more effective against 4T1 cells than the parental virus or a reference oncolytic VSV (MΔ51), but showed no increased efficacy against CT26 cells. In vivo assays using 4T1 syngeneic tumor models showed that one of the evolved lines significantly delayed tumor growth compared to mice treated with the parental virus or untreated controls, and was able to induce transient tumor suppression. Our results show that RNA viruses can be specifically adapted typical cancer features such as p53 inactivation, and illustrate the usefulness of experimental evolution for oncolytic virotherapy

Architecture and roles of periplasmic adaptor proteins in tripartite efflux assemblies.

Recent years have seen major advances in the structural understanding of the different components of tripartite efflux assemblies, which encompass the multidrug efflux (MDR) pumps and type I secretion systems. The majority of these investigations have focused on the role played by the inner membrane transporters and the outer membrane factor (OMF), leaving the third component of the system - the Periplasmic Adaptor Proteins (PAPs) - relatively understudied. Here we review the current state of knowledge of these versatile proteins which, far from being passive linkers between the OMF and the transporter, emerge as active architects of tripartite assemblies, and play diverse roles in the transport process. Recognition between the PAPs and OMFs is essential for pump assembly and function, and targeting this interaction may provide a novel avenue for combating multidrug resistance. With the recent advances elucidating the drug efflux and energetics of the tripartite assemblies, the understanding of the interaction between the OMFs and PAPs is the last piece remaining in the complete structure of the tripartite pump assembly puzzle

Service planning and delivery outcomes of home adaptations for ageing in the UK

In response to the impact of demographic change on the healthcare system, ‘ageing in place’ was introduced as a national policy to support elderly people living independently in their homes. Housing adaptation is essential for successful independent living and has been given increased political priority. However, adaptation policies and practice vary regionally, reflecting statutory limits, policy choices and local planning. This study investigated the current status of adaptation provision in different regions in the UK and assessed the effectiveness of local service planning and management. A mixed-methods sequential explanatory research strategy was employed. In the first quantitative phase, a questionnaire survey was carried out involving all 378 local authorities in England, Scotland and Wales. This was followed by a second qualitative phase involving individual interviews with five professionals and two clients and a focus group meeting with six key stakeholders. The study found that the current number of adaptations was relatively small compared with potential demands in most local areas, as was funding for adaptations. On the operational side, the adaptation process was fragmented, involving different service groups in many local authorities. There were disconnections between these groups, which often caused inefficiencies and poor effectiveness. Moving forward, local authorities need to have a clear vision of the overall need for adaptations and allocate sufficient resources. Practical guidelines are also needed for better integrated working and performance management

The Rift Valley fever accessory proteins NSm and P78/NSm-GN are distinct determinants of virus propagation in vertebrate and invertebrate hosts.: Role of NSm-related proteins in RVFV infection

International audienceRift Valley fever virus (RVFV) is an enzootic virus circulating in Africa that is transmitted to its vertebrate host by a mosquito vector and causes severe clinical manifestations in humans and ruminants. RVFV has a tripartite genome of negative or ambisense polarity. The M segment contains five in-frame AUG codons that are alternatively used for the synthesis of two major structural glycoproteins, GN and GC, and at least two accessory proteins, NSm, a 14-kDa cytosolic protein, and P78/NSm-GN, a 78-kDa glycoprotein. To determine the relative contribution of P78 and NSm to RVFV infectivity, AUG codons were knocked out to generate mutant viruses expressing various sets of the M-encoded proteins. We found that, in the absence of the second AUG codon used to express NSm, a 13-kDa protein corresponding to an N-terminally truncated form of NSm, named NSm', was synthesized from AUG 3. None of the individual accessory proteins had any significant impact on RVFV virulence in mice. However, a mutant virus lacking both NSm and NSm' was strongly attenuated in mice and grew to reduced titers in murine macrophages, a major target cell type of RVFV. In contrast, P78 was not associated with reduced viral virulence in mice, yet it appeared as a major determinant of virus dissemination in mosquitoes. This study demonstrates how related accessory proteins differentially contribute to RVFV propagation in mammalian and arthropod hosts

Intermediate care at a community hospital as an alternative to prolonged general hospital care for elderly patients: a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Demographic changes together with an increasing demand among older people for hospital beds and other health services make allocation of resources to the most efficient care level a vital issue. The aim of this trial was to study the efficacy of intermediate care at a community hospital compared to standard prolonged care at a general hospital.</p> <p>Methods</p> <p>In a randomised controlled trial 142 patients aged 60 or more admitted to a general hospital due to acute illness or exacerbation of a chronic disease 72 (intervention group) were randomised to intermediate care at a community hospital and 70 (general hospital group) to further general hospital care.</p> <p>Results</p> <p>In the intervention group 14 patients (19.4%) were readmitted for the same disease compared to 25 patients (35.7%) in the general hospital group (p = 0.03). After 26 weeks 18 (25.0%) patients in the intervention group were independent of community care compared to seven (10.0%) in the general hospital group (p = 0.02). There were an insignificant reduction in the number of deaths and an insignificant increase in the number of days with inward care in the intervention group. The number of patients admitted to long-term nursing homes from the intervention group was insignificantly higher than from the general hospital group.</p> <p>Conclusion</p> <p>Intermediate care at a community hospital significantly decreased the number of readmissions for the same disease to general hospital, and a significantly higher number of patients were independent of community care after 26 weeks of follow-up, without any increase in mortality and number of days in institutions.</p

Experimental Passage of St. Louis Encephalitis Virus In Vivo in Mosquitoes and Chickens Reveals Evolutionarily Significant Virus Characteristics

St. Louis encephalitis virus (SLEV; Flaviviridae, flavivirus) was the major cause of epidemic flaviviral encephalitis in the U.S. prior to the introduction of West Nile virus (WNV) in 1999. However, outbreaks of SLEV have been significantly more limited then WNV in terms of levels of activity and geographic dispersal. One possible explanation for these variable levels of activity is that differences in the potential for each virus to adapt to its host cycle exist. The need for arboviruses to replicate in disparate hosts is thought to result in constraints on both evolution and host-specific adaptation. If cycling is the cause of genetic stability observed in nature and arboviruses lack host specialization, then sequential passage should result in both the accumulation of mutations and specialized viruses better suited for replication in that host. Previous studies suggest that WNV and SLEV differ in capacity for both genetic change and host specialization, and in the costs each accrues from specializing. In an attempt to clarify how selective pressures contribute to epidemiological patterns of WNV and SLEV, we evaluated mutant spectra size, consensus genetic change, and phenotypic changes for SLEV in vivo following 20 sequential passages via inoculation in either Culex pipiens mosquitoes or chickens. Results demonstrate that the capacity for genetic change is large for SLEV and that the size of the mutant spectrum is host-dependent using our passage methodology. Despite this, a general lack of consensus change resulted from passage in either host, a result that contrasts with the idea that constraints on evolution in nature result from host cycling alone. Results also suggest that a high level of adaptation to both hosts already exists, despite host cycling. A strain significantly more infectious in chickens did emerge from one lineage of chicken passage, yet other lineages and all mosquito passage strains did not display measurable host-specific fitness gains. In addition, increased infectivity in chickens did not decrease infectivity in mosquitoes, which further contrasts the concept of fitness trade-offs for arboviruses