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The Adapted Forestry Regime (AFR) of the Paix des Braves agreement is an important stepping-stone in the long process of involving Indigenous Peoples in state management of forestlands in Canada. This paper explores the challenges raised by a process involving the Cree nation and the Québec provincial government in the implementation of a collaborative approach to forest management on Cree traditional lands. We present three key processes that have contributed to the AFR since 2002, each of which led to further agreements, committees and processes. While the Crees have obtained additional powers for forestland management through the AFR, our analysis reveals the complexity of these processes that must deal with both political and technical issues that are often closely intricated one with the other. Ultimately, it is the Crees who bear the heaviest burden of the compromises that must be made implementing this collaborative process.

This Special Issue aims to provide an overview of the diversity of international research on the multiple ways in which Indigenous and Traditional peoples (ITP) are engaged in occupying and governing forest landscapes, consistent with their rights, values, knowledge and customs. This Introduction begins by reviewing our evolving understanding of two key questions: what rights are held by ITP; and how "Indigenous" and "Traditional" are actually defined. Papers in this Special Issue examine different concepts in more than a dozen countries on five continents and, while each study and each people is distinct, we identify several common themes. Firstly, traditional knowledge, values, and practices are central to the relationship between ITP and forest landscapes and underlie the effectiveness of other interventions. Secondly, early efforts to use forests to promote economic development have given way to a deeper understanding of the ways in which diverse products, services, and cultural values of forest landscapes support livelihoods for both ITP and other populations. Thirdly, governance is a common theme in this Special Issue, especially in terms of relations between ITP and the State and in the effectiveness of policies and programs. A fourth theme is that of understanding how the knowledge, practices and values of individuals and groups can help predict perceptions of forests and preferences for management. Finally, this Special Issue showcases a wide variety of methodological approaches, both qualitative and quantitative, helping researchers recognize the advantages and limits of each. Taken together, the papers in this Special Issue illustrate multiple characteristics of relationships between ITP and forest landscapes, and their aspirations to maintain their culture, their knowledge, their rights, and their livelihoods.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): This study is funded by Bayer PLC, 400 South Oak Way, Green Park, Reading, Berkshire, RG2 6AD. Background Impaired endogenous fibrinolysis is novel biomarker that can identify patients with ACS at increased cardiovascular risk. The addition of very low dose rivaroxaban (VLDR) to dual antiplatelet therapy has been shown to reduce cardiovascular events but at a cost of increased bleeding and is therefore not suitable for all-comers. Targeted additional pharmacotherapy with VLDR to improve endogenous fibrinolysis may improve outcomes in high-risk patients, whilst avoiding unnecessary bleeding in low-risk individuals. Methods and Results The VaLiDate-R study is an investigator-initiated, randomised, open-label, single centre trial comparing the effect of 3 antithrombotic regimens on endogenous fibrinolysis in 150 patients with ACS. Subjects whose screening blood test shows impaired fibrinolytic status (lysis time >2000s), will be randomised to one of 3 treatment arms in a 1:1:1 ratio: clopidogrel 75 mg daily (Group 1); clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily (Group 2); ticagrelor 90 mg twice daily (Group 3), in addition to aspirin 75 mg daily. Rivaroxaban will be given for 30 days. Fibrinolytic status will be assessed during admission and at 2, 4 and 8 weeks. The primary outcome measure is the change in fibrinolysis time from admission to 4 weeks follow-up, using the Global Thrombosis Test. Conclusion If VLDR can improve endogenous fibrinolysis in ACS, future large-scale studies would be required to assess whether targeted use of VLDR in patients with ACS and impaired fibrinolysis can translate into improved clinical outcomes, with reduction in major adverse cardiovascular events in this high-risk cohort.

We present photometric and spectroscopic data on three extragalactic luminous red novae (LRNe): AT 2018bwo, AT 2021afy, and AT 2021blu. AT 2018bwo was discovered in NGC 45 (at about 6.8 Mpc) a few weeks after the outburst onset. During the monitoring period, the transient reached a peak luminosity of 1040 erg s−1. AT 2021afy, hosted by UGC 10043 (∼49.2 Mpc), showed a double-peaked light curve, with the two peaks reaching a similar luminosity of 2.1(±0.6)×1041 erg s−1. Finally, for AT 2021blu in UGC 5829 (∼8.6 Mpc), the pre-outburst phase was well-monitored by several photometric surveys, and the object showed a slow luminosity rise before the outburst. The light curve of AT 2021blu was sampled with an unprecedented cadence until the object disappeared behind the Sun, and it was then recovered at late phases. The light curve of LRN AT 2021blu shows a double peak, with a prominent early maximum reaching a luminosity of 6.5 × 1040 erg s−1, which is half of that of AT 2021afy. The spectra of AT 2021afy and AT 2021blu display the expected evolution for LRNe: a blue continuum dominated by prominent Balmer lines in emission during the first peak, and a redder continuum consistent with that of a K-type star with narrow absorption metal lines during the second, broad maximum. The spectra of AT 2018bwo are markedly different, with a very red continuum dominated by broad molecular features in absorption. As these spectra closely resemble those of LRNe after the second peak, AT 2018bwo was probably discovered at the very late evolutionary stages. This would explain its fast evolution and the spectral properties compatible with that of an M-type star. From the analysis of deep frames of the LRN sites years before the outburst, and considerations of the light curves, the quiescent progenitor systems of the three LRNe were likely massive, with primaries ranging from about 13 M⊙ for AT 2018bwo, to 14−1+4 M⊙ for AT 2021blu, and over 40 M⊙ for AT 2021afy.

We present deep Chandra X-ray observations of two nearby Type Ia supernovae, SN 2017cbv and SN 2020nlb, which reveal no X-ray emission down to a luminosity $L_X$$\lesssim$5.3$\times$10$^{37}$ and $\lesssim$5.4$\times$10$^{37}$ erg s$^{-1}$ (0.3--10 keV), respectively, at $\sim$16--18 days after the explosion. With these limits, we constrain the pre-explosion mass-loss rate of the progenitor system to be $\dot{M}$$, Comment: 19 pages, 6 figures, ApJ Accepted

The American Water Works Association (AWWA) has developed and disseminated advanced methods and performance indicators for assessing and reducing water losses in North America, based in large part on the methods and indicators developed by the International Water Association (IWA). However, many utilities and regulators still use the old, inaccurate, %NRW indicator. A robust, quantitative assessment of the technical rigor of water loss indicators was needed but could not be found in the literature. So, an innovative approach was developed, using Frontier Analysis which provided such a score of ‘technical rigor’. This paper presents this method, applied to three datasets from North America, assessing 15 candidate indicators for total water losses, apparent losses and real losses. The results provide quantitative ‘scores’ of the technical rigor of the candidate indicators. Indicators with relatively high scores align with indicators used in the IWA best practices. Other indicators, such as the %NRW indicator, were found to have low technical rigor. The conclusion of the paper summarizes the rigorous indicators, and suggests areas for further application of this method, and for further research.

Modified vaccinia virus Ankara (MVA) was derived by repeated passaging in chick fibroblasts, during which deletions and mutations rendered the virus unable to replicate in most mammalian cells. Marker rescue experiments demonstrated that the host range defect could be overcome by replacing DNA that had been deleted from near the left end of the genome. One virus isolate, however, recovered the ability to replicate in monkey BS-C-1 cells but not human cells without added DNA, suggesting that it arose from a spontaneous mutation. Here, we showed that variants with enhanced ability to replicate in BS-C-1 cells could be isolated by blind passaging of MVA and that in each there was a point mutation leading to an amino acid substitution in the D10 decapping enzyme. The sufficiency of these single mutations to enhance host range was confirmed by constructing recombinant viruses. The D10 mutations occurred at N- or C-terminal locations distal to the active site, suggesting an indirect effect on decapping or on another previously unknown role of D10. Although increased amounts of viral mRNA and proteins were found in BS-C-1 cells infected with the mutants compared to those with parental MVA, the increases were much less than the 1- to 2-log-higher virus yields. Nevertheless, a contributing role for diminished decapping in overcoming the host range defect was consistent with increased replication and viral protein synthesis in BS-C-1 cells infected with an MVA engineered to have active-site mutations that abrogate decapping activity entirely. Optimal decapping may vary depending on the biological context. IMPORTANCE Modified vaccinia virus Ankara (MVA) is an attenuated virus that is approved as a smallpox vaccine and is in clinical trials as a vector for other pathogens. The safety of MVA is due in large part to its inability to replicate in mammalian cells. Although host range restriction is considered a stable feature of the virus, we describe the occurrence of spontaneous mutations in MVA that increase replication considerably in monkey BS-C-1 cells but only slightly in human cells. The mutants contain single nucleotide changes that lead to amino acid substitutions in one of the two decapping enzymes. Although the spontaneous mutations are distant from the decapping enzyme active site, engineered active-site mutations also increased virus replication in BS-C-1 cells. The effects of these mutations on the immunogenicity of MVA vectors remain to be determined.

Funding: We gratefully acknowledge funding from VILLUM FONDEN through the Young Investigator Program (Grant. No.15375) and the Centre of Excellence for Dirac Materials (Grant. No. 11744), the Danish Council for Independent Research, Natural Sciences under the Sapere Aude program (Grant Nos. DFF-9064-00057B and DFF-6108-00409) and the Aarhus University Research Foundation. This work is also supported by National Research Foundation (NRF) grants funded by the Korean government (nos. NRF-2020R1A2C200373211 and 2019K1A3A7A09033389) and by the International MaxPlanck Research School for Chemistry and Physics of Quantum Materials (IMPRS-CPQM). The authors also acknowledge The Royal Society and The Leverhulme Trust. R.S acknowledges financial support provided by the Ministry of Science and Technology in Taiwan under project number MOST-108-2112-M-001-049-MY2 & MOST 109-2124-M-002-001 and Sinica funded i-MATE financial Support AS-iMATE-109-13. Access to the Artemis Facility was funded by STFC. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231.

The transition-metal dichalcogenide VSe

The Steward Alerts for Science System (SASSy) supports transient science by ingesting alerts from various sources. Cross-referencing using Q3C spatial indexing is enabled on most database tables allowing astronomers to explore the data in a variety of ways. SassyCron, a layered application, is a specific targeted search to find promising early supernovae candidates and request spectra from telescopes available to Steward Observatory science staff.

Modified vaccinia virus Ankara (MVA) is an approved smallpox vaccine and a promising vaccine vector for other pathogens as well as for cancer therapeutics with more than 200 current or completed clinical trials. MVA was derived by passaging the parental Ankara vaccine virus hundreds of times in chick embryo fibroblasts during which it lost the ability to replicate in human and most other mammalian cells. Although this replication deficiency is an important safety feature, the genetic basis of the host restriction is not understood. Here, an unbiased human genome-wide RNAi screen in human A549 cells revealed that the zinc-finger antiviral protein (ZAP), previously shown to inhibit certain RNA viruses, is a host restriction factor for MVA, a DNA virus. Additional studies demonstrated enhanced MVA replication in several human cell lines following knockdown of ZAP. Furthermore, CRISPR-Cas9 knockout of ZAP in human A549 cells increased MVA replication and spread by more than one log but had no effect on a non-attenuated strain of vaccinia virus. The intact viral C16 protein, which had been disrupted in MVA, antagonized ZAP by binding and sequestering the protein in cytoplasmic punctate structures. Studies aimed at exploring the mechanism by which ZAP restricts MVA replication in the absence of C16 showed that knockout of ZAP had no discernible effect on viral DNA or individual mRNA or protein species as determined by droplet digital polymerase chain reaction, deep RNA sequencing and mass spectrometry, respectively. Instead, inactivation of ZAP reduced the number of aberrant, dense, spherical particles that typically form in MVA-infected human cells, suggesting that ZAP has a novel role in interfering with a late step in the assembly of infectious MVA virions in the absence of the C16 protein., Author summary The attenuated vaccine vector known as modified vaccinia virus Ankara (MVA) was derived by extensively passaging the parental strain of vaccinia virus Ankara in chick embryo fibroblasts and is unable to replicate in most mammalian cells. The MVA host range restriction is exceptional in that synthesis of the abundant viral proteins appears unaffected but morphogenesis of virus particles is abortive. Despite the importance of the host range restriction for vaccine safety, the basis for this antiviral effect has remained an enigma. Here we demonstrate that the zinc finger antiviral protein (ZAP), previously shown to be an inhibitor of RNA viruses, is a specific host restriction factor for replication of MVA in human cells. Moreover, the intact vaccinia virus C16 protein, which was disrupted during the attenuation of MVA, sequesters ZAP in cytoplasmic punctae and effectively counteracts the inhibitory effects of ZAP.

DNA-based vaccines able to induce efficient cytotoxic T-cell responses targeting conserved elements (CE) of human immunodeficiency virus type 1 (HIV-1) Gag have been developed. These CE were selected by stringent conservation, the ability to induce T-cell responses with broad human leukocyte antigen coverage, and the association between recognition of CE epitopes and viral control in HIV-infected individuals. Based on homology to HIV, a simian immunodeficiency virus p27gag CE DNA vaccine has also been developed. This study reports on the durability of the CE-specific T-cell responses induced by HIV and simian immunodeficiency virus CE DNA-based prime/boost vaccine regimens in rhesus macaques, and shows that the initially primed CE-specific T-cell responses were efficiently boosted by a single CE DNA vaccination after the long rest period (up to 2 years). In another cohort of animals, the study shows that a single inoculation with non-replicating recombinant Modified Vaccinia Ankara (rMVA62B) also potently boosted CE-specific responses after around 1.5 years of rest. Both CE DNA and rMVA62B booster vaccinations increased the magnitude and cytotoxicity of the CE-specific responses while maintaining the breadth of CE recognition. Env produced by rMVA62B did not negatively interfere with the recall of the Gag CE responses. rMVA62B could be beneficial to further boosting the immune response to Gag in humans. Vaccine regimens that employ CE DNA as a priming immunogen hold promise for application in HIV prevention and therapy.

Environmental, social, and governance (ESG) issues have become a core business concern and a central focus of investors. The ESG reporting landscape is fragmented, with hundreds of reporting standards forming what has been called an alphabet soup of acronyms with no common framework to guide corporate disclosures. Companies’ ESG disclosures vary widely and investors complain that they do not have the comparable, decision-useful information that they need to properly factor ESG considerations into their investment decisions. For their part, companies express concern over the lack of guidance as to which disclosure standards to follow. The SEC’s reporting rules have remained essentially unchanged for decades even amid calls for reform. At the same time, organizations, including the World Economic Forum, have called for efforts to bring consistency and comparability to ESG disclosures. This chapter explores this dynamic landscape and anticipates significant change in the regulation of ESG reporting over the coming years.

Assembling transition metal dichalcogenides (TMDCs) at the two-dimensional (2D) limit is a promising approach for tailoring emerging states of matter such as superconductivity or charge density waves (CDWs). Single-layer (SL) VSe$_2$ stands out in this regard because it exhibits a strongly enhanced CDW transition with a higher transition temperature compared to the bulk in addition to an insulating phase with an anisotropic gap at the Fermi level, causing a suppression of anticipated 2D ferromagnetism in the material. Here, we investigate the interplay of electronic and lattice degrees of freedom that underpin these electronic phases in SL VSe$_2$ using ultrafast pump-probe photoemission spectroscopy. In the insulating state, we observe a light-induced closure of the energy gap on a timescale of 480 fs, which we disentangle from the ensuing hot carrier dynamics. Our work thereby reveals that the phase transition in SL VSe$_2$ is driven by electron-lattice coupling and demonstrates the potential for controlling electronic phases in 2D materials with light., Comment: 23 pages including supplementary information, 3 figures in the main text and 6 figures in the supplemental text

We present early-time ($t < +50$ days) observations of SN 2019muj (= ASASSN-19tr), one of the best-observed members of the peculiar SN Iax class. Ultraviolet and optical photometric and optical and near-infrared spectroscopic follow-up started from $\sim$5 days before maximum light ($t_{max}(B)$ on $58707.8$ MJD) and covers the photospheric phase. The early observations allow us to estimate the physical properties of the ejecta and characterize the possible divergence from a uniform chemical abundance structure. The estimated bolometric light curve peaks at 1.05 $\times$ 10$^{42}$ erg s$^{-1}$ and indicates that only 0.031 $M_\odot$ of $^{56}$Ni was produced, making SN 2019muj a moderate luminosity object in the Iax class with peak absolute magnitude of $M_{V}$ = -16.4 mag. The estimated date of explosion is $t_0 = 58698.2$ MJD and implies a short rise time of $t_{rise}$ = 9.6 days in $B$-band. We fit of the spectroscopic data by synthetic spectra, calculated via the radiative transfer code TARDIS. Adopting the partially stratified abundance template based on brighter SNe Iax provides a good match with SN 2019muj. However, without earlier spectra, the need for stratification cannot be stated in most of the elements, except carbon, which is allowed to appear in the outer layers only. SN 2019muj provides a unique opportunity to link extremely low-luminosity SNe Iax to well-studied, brighter SNe Iax., 24 pages, 17 figures, accepted for publication in MNRAS

With the conclusion of the third observing run for Advanced LIGO/Virgo (O3), we present a detailed analysis of both triggered and serendipitous observations of 17 gravitational wave (GW) events (7 triggered and 10 purely serendipitous) from the Searches After Gravitational-waves Using ARizona Observatories (SAGUARO) program. We searched a total of 4935 deg$^2$ down to a median 5$��$ transient detection depth of 21.1 AB mag using the Mt Lemmon 1.5 m telescope, the discovery engine for SAGUARO. In addition to triggered events within 24~hours, our transient search encompassed a time interval following GW events of $, 44 pages, 21 figures, 2 tables, submitted to ApJ

The dissociation dynamics of CH

Research by D.J.S. is supported by NSF grants AST-1821967, AST-1821987, AST-1813708, AST-1813466, and AST-1908972, as well as by the Heising-Simons Foundation under grant #20201864. The CSP-II has been supported by National Science Foundation (NSF) grants AST-1008343, AST-1613426, AST-1613455, and AST-1613472, as well as by the Danish Agency for Science and Technology and Innovation through a Sapere Aude Level 2 grant. E.Y.H. and J.L. also acknowledge the support of the Florida Space Grant Consortium. This work was partially performed at the Aspen Center for Physics, which is supported by NSF grant PHY-1607611. Research by S.V. is supported by NSF grants AST1813176 and AST-2008108. L.G. was funded by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 839090. This work has been partially supported by the Spanish grant PGC2018-095317-B-C21 within the European Funds for Regional Development (FEDER). M.S. is supported by generous grants from Villum FONDEN (13261, 28021) and by a project grant (8021-00170B) from the Independent Research Fund Denmark. A.V.F. is grateful for financial assistance from the TABASGO Foundation, the Christopher R. Redlich Fund, and the Miller Institute for Basic Research in Science (U.C. Berkeley). Based on observations obtained at the international Gemini Observatory (GN-2015A-Q-8, GS-2015A-Q-5), a program of NSF's NOIRLab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation. on behalf of the Gemini Observatory partnership: the National Science Foundation (United States), National Research Council (Canada), Agencia Nacional de Investigacion y Desarrollo (Chile), Ministerio de Ciencia, Tecnologia e Innovacion (Argentina), Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea). This paper includes data gathered with the Nordic Optical Telescope (PI Stritzinger) at the Observatorio del Roque de los Muchachos, La Palma, Spain. This work is based in part on observations from the Deep Imaging Multi-Object Spectrograph at the Keck II telescope. We are grateful to the staff at the Keck Observatory for their assistance, and we extend special thanks to those of Hawaiian ancestry on whose sacred mountain we are privileged to be guests. The W. M. Keck Observatory is operated as a scientific partnership among the California Institute of Technology, the University of California, and NASA; it was made possible by the generous financial support of the W. M. Keck Foundation. We thank S. Bradley Cenko for assistance with the Keck spectral reductions, as well as Patrick Kelly, WeiKang Zheng, and John Mauerhan for their assistance with the observations. D.J.S. is a visiting Astronomer at the Infrared Telescope Facility, which is operated by the University of Hawaii under contract 80HQTR19D0030 with the National Aeronautics and Space Administration. Based on data products from observations made with ESO Telescopes at the La Silla Paranal Observatory under programmes 188.D-3003 and 191.D-0935: PESSTO (the Public ESO Spectroscopic Survey for Transient Objects)., Unburned carbon is potentially a powerful probe of Type Ia supernova (SN) explosion mechanisms. We present comprehensive optical and near-infrared (NIR) data on the "transitional" Type Ia SN 2015bp. An early NIR spectrum (t=−9.9 days with respect to B-band maximum) displays a striking C I λ1.0693μm line at 11.9×103~km s−1, distinct from the prominent Mg II λ1.0927μm feature, which weakens toward maximum light. SN 2015bp also displays a clear C II λ6580A notch early (t=−10.9 days) at 13.2×103~km s−1, consistent with our NIR carbon detection. At MB=−18.46, SN 2015bp is less luminous than a normal SN Ia and, along with iPTF13ebh, is the second member of the transitional subclass to display prominent early-time NIR carbon absorption. We find it unlikely that the C I feature is misidentified He I λ1.0830μm because this feature grows weaker toward maximum light, while the helium line produced in some double-detonation models grows stronger at these times. Intrigued by these strong NIR carbon detections, but lacking NIR data for other SNe Ia, we investigated the incidence of optical carbon in the sample of nine transitional SNe Ia with early-time data (t≲−4 days). We find that four display C II λ6580A, while two others show tentative detections, in line with the SN Ia population as a whole. We conclude that at least ∼50% of transitional SNe Ia in our sample do not come from sub-Chandrasekhar mass explosions due to the clear presence of carbon in their NIR and optical spectra., National Science Foundation (NSF) AST-1821967 AST-1821987 AST-1813708 AST-1813466 AST-1908972 PHY-1607611 AST1813176 AST-2008108, Heising-Simons Foundation 20201864, National Science Foundation (NSF) AST-1008343 AST-1613426 AST-1613455 AST-1613472, Danish Agency for Science and Technology and Innovation, Florida Space Grant Consortium, European Commission 839090, Spanish grant within the European Funds for Regional Development (FEDER) PGC2018-095317-B-C21, Villum Foundation 13261 28021, Independent Research Fund Denmark 8021-00170B, TABASGO Foundation, Christopher R. Redlich Fund, Miller Institute for Basic Research in Science (U.C. Berkeley), International Gemini Observatory GN-2015A-Q-8 GS-2015A-Q-5, W.M. Keck Foundation, University of Hawaii 80HQTR19D0030, National Aeronautics & Space Administration (NASA), ESO Telescopes at the La Silla Paranal Observatory 188.D-3003 191.D-0935: PESSTO

We tested, in rhesus macaques, the effects of a 500-fold range of an admixed recombinant modified vaccinia Ankara (MVA) expressing rhesus GM-CSF (MVA/GM-CSF) on the immunogenicity and protection elicited by an MVA/SIV macaque 239 vaccine. High doses of MVA/GM-CSF did not affect the levels of systemic envelope (Env)-specific Ab, but it did decrease the expression of the gut-homing receptor α4β7 on plasmacytoid dendritic cells (p < 0.01) and the magnitudes of Env-specific IgA (p = 0.01) and IgG (p < 0.05) in rectal secretions. The protective effect of the vaccine was evaluated using 12 weekly rectal challenges in rhesus macaques subgrouped by tripartite motif-containing protein 5α (TRIM5α) genotypes that are restrictive or permissive for infection by the challenge virus SIVsmE660. Eight of nine TRIM5α-restrictive animals receiving no or the lowest dose (1 × 105 PFU) of MVA/GM-CSF resisted all 12 challenges. In the comparable TRIM5α-permissive group, only 1 of 12 animals resisted all 12 challenges. In the TRIM5α-restrictive animals, but not in the TRIM5α-permissive animals, the number of challenges to infection directly correlated with the magnitudes of Env-specific rectal IgG (r = +0.6) and IgA (r = +0.6), the avidity of Env-specific serum IgG (r = +0.5), and Ab dependent cell-mediated virus inhibition (r = +0.6). Titers of neutralizing Ab did not correlate with protection. We conclude that 1) protection elicited by MVA/SIVmac239 is strongly dependent on the presence of TRIM5α restriction, 2) nonneutralizing Ab responses contribute to protection against SIVsmE660 in TRIM5α-restrictive animals, and 3) high doses of codelivered MVA/GM-CSF inhibit mucosal Ab responses and the protection elicited by MVA expressing noninfectious SIV macaque 239 virus-like particles.

We present the results of our monitoring campaigns of the luminous red novae (LRNe) AT 2020hat in NGC 5068 and AT 2020kog in NGC 6106. The two objects were imaged (and detected) before their discovery by routine survey operations. They show a general trend of slow luminosity rise, lasting at least a few months. The subsequent major LRN outbursts were extensively followed in photometry and spectroscopy. The light curves present an initial short-duration peak, followed by a redder plateau phase. AT 2020kog is a moderately luminous event peaking at ∼7 × 1040 erg s−1, while AT 2020hat is almost one order of magnitude fainter than AT 2020kog, although it is still more luminous than V838 Mon. In analogy with other LRNe, the spectra of AT 2020kog change significantly with time. They resemble those of type IIn supernovae at early phases, then they become similar to those of K-type stars during the plateau, and to M-type stars at very late phases. In contrast, AT 2020hat already shows a redder continuum at early epochs, and its spectrum shows the late appearance of molecular bands. A moderate-resolution spectrum of AT 2020hat taken at +37 d after maximum shows a forest of narrow P Cygni lines of metals with velocities of 180 km s−1, along with an Hα emission with a full-width at half-maximum velocity of 250 km s−1. For AT 2020hat, a robust constraint on its quiescent progenitor is provided by archival images of the Hubble Space Telescope. The progenitor is clearly detected as a mid-K type star, with an absolute magnitude of MF606W = −3.33 ± 0.09 mag and a colour of F606W − F814W = 1.14 ± 0.05 mag, which are inconsistent with the expectations from a massive star that could later produce a core-collapse supernova. Although quite peculiar, the two objects nicely match the progenitor versus light curve absolute magnitude correlations discussed in the literature.

The inability of species to adapt to changing climate may cause ecological communities to disassemble and lose ecological functioning. However, theory suggests that communities may be resilient whenever populations within species exhibit variation in thermal plasticity or adaptation whereby thermally tolerant populations replace thermally sensitive ones. But will they maintain the functional roles of the populations being replaced? This study evaluated whether "like replaces like" functionally by measuring how four populations of a grasshopper herbivore and its co-occurring spider predator cope with environmental warming. The study occurred across a latitudinal gradient bounded by southerly, warmer Connecticut and northerly, cooler New Hampshire, USA. The study compared the survival rates, thermal performance, habitat usage, and food chain interactions of each grasshopper and spider population between its home field site (field of origin) and a Connecticut transplant site, and the native Connecticut population. Three grasshopper populations exhibited physiological plasticity by adjusting metabolic rates. The fourth population selected cooler habitat locations. Spider populations did not alter their metabolism and instead selected cooler habitat locations, thereby altering spatial overlap with their prey and food chain interactions. Grasshopper populations that coped physiologically consumed plants in different ratios than the fourth population and the Connecticut population. Hence, "like may not replace like" whenever populations adapt physiologically to warming.

Modified vaccinia virus Ankara (MVA), an attenuated poxvirus, has been developed as a potential vaccine vector for use against cancer and multiple infectious diseases, including human immunodeficiency virus (HIV). MVA is highly immunogenic and elicits strong cellular and humoral responses in preclinical models and humans. However, there is potential to further enhance the immunogenicity of MVA, as MVA-infected cells undergo rapid apoptosis, leading to faster clearance of recombinant antigens and potentially blunting a greater response. Here, we generated MVA-B13R by replacing the fragmented 181R/182R genes of MVA with a functional anti-apoptotic gene, B13R, and confirmed its anti-apoptotic function against chemically induced apoptosis in vitro In addition, MVA-B13R showed a significant delay in induction of apoptosis in muscle cells derived from mice and humans, as well as in plasmacytoid dendritic cells (pDCs) and CD141+ DCs from rhesus macaques, compared to the induction of apoptosis in MVA-infected cells. MVA-B13R expressing simian immunodeficiency virus (SIV) Gag and Pol and HIV envelope (SHIV) (MVA-B13R/SHIV) produced higher levels of envelope in the supernatants than MVA/SHIV-infected DF-1 cells in vitro Immunization of BALB/c mice showed induction of higher levels of envelope-specific antibody-secreting cells and memory B cells, higher IgG antibody titers, and better persistence of antibody titers with MVA-B13R/SHIV than with MVA/SHIV. Gene set enrichment analysis of draining lymph node cells from day 1 after immunization showed negative enrichment for interferon responses in MVA-B13R/SHIV-immunized mice compared to the responses in MVA/SHIV-immunized mice. Taken together, these results demonstrate that restoring B13R functionality in MVA significantly delays MVA-induced apoptosis in muscle and antigen-presenting cells in vitro and augments vaccine-induced humoral immunity in mice.IMPORTANCE MVA is an attractive viral vector for vaccine development due to its safety and immunogenicity in multiple species and humans even under conditions of immunodeficiency. Here, to further improve the immunogenicity of MVA, we developed a novel vector, MVA-B13R, by replacing the fragmented anti-apoptotic genes 181R/182R with a functional version derived from vaccinia virus, B13R Our results show that MVA-B13R significantly delays apoptosis in antigen-presenting cells and muscle cells in vitro and augments vaccine-induced humoral immunity in mice, leading to the development of a novel vector for vaccine development against infectious diseases and cancer.

We present Searches After Gravitational-waves Using ARizona Observatories (SAGUARO), a comprehensive effort dedicated to the discovery and characterization of optical counterparts to gravitational wave (GW) events. SAGUARO utilizes ground-based facilities ranging from 1.5m to 10m in diameter, located primarily in the Northern Hemisphere. We provide an overview of SAGUARO's telescopic resources, pipeline for transient detection, and database for candidate visualization. We describe SAGUARO's discovery component, which utilizes the $5$~deg$^2$ field-of-view optical imager on the Mt. Lemmon 1.5m telescope, reaching limits of $\approx 21.3$~AB mag while rapidly tiling large areas. We also describe the follow-up component of SAGUARO, used for rapid vetting and monitoring of optical candidates. With the onset of Advanced LIGO/Virgo's third observing run, we present results from the first three SAGUARO searches following the GW events S190408an, S190425z and S190426c, which serve as a valuable proof-of-concept of SAGUARO. We triggered and searched 15, 60 and 60 deg$^{2}$ respectively, 17.6, 1.4 and 41.8 hrs after the initial GW alerts. We covered 7.8, 3.0 and 5.1\% of the total probability within the GW event localizations, reaching 3$\sigma$ limits of 19.8, 21.3 and 20.8 AB mag, respectively. Although no viable counterparts associated with these events were found, we recovered 6 known transients and ruled out 5 potential candidates. We also present Large Binocular Telescope spectroscopy of PS19eq/SN2019ebq, a promising kilonova candidate that was later determined to be a supernova. With the ability to tile large areas and conduct detailed follow-up, SAGUARO represents a significant addition to GW counterpart searches., Comment: 16 pages, 7 figures, 1 table. Accepted to ApJL

We present the discovery and high-cadence follow-up observations of SN 2018ivc, an unusual Type II supernova that exploded in NGC 1068 (D=10.1 Mpc). The light curve of SN 2018ivc declines piecewise-linearly, changing slope frequently, with four clear slope changes in the first 30 days of evolution. This rapidly changing light curve indicates that interaction between the circumstellar material and ejecta plays a significant role in the evolution. Circumstellar interaction is further supported by a strong X-ray detection. The spectra are rapidly evolving and dominated by hydrogen, helium, and calcium emission lines. We identify a rare high-velocity emission-line feature blueshifted at ~7800 km/s (in Ha, Hb, Pb, Pg, HeI, CaII), which is visible from day 18 until at least day 78 and could be evidence of an asymmetric progenitor or explosion. From the overall similarity between SN 2018ivc and SN 1996al, the \Ha{} equivalent width of its parent HII region, and constraints from pre-explosion archival Hubble Space Telescope images, we find that the progenitor of SN 2018ivc could be as massive as 52 Msun but is more likely, Accepted by ApJ. Revised version includes more extensive progenitor analysis

Objective To observe rates of returns and to identify trends in returns of potentially abused medications during medication take-back events. Methods A retrospective cross-sectional study was conducted of returned medications during medication take-back days from 2013 to 2016 based on a partnership between local law enforcement and a school of pharmacy in a rural South Carolina town. Data collected on returned items included active ingredients, estimated quantity, and prescription fill date if available. The medications were classified by therapeutic class and further identified drugs of potential abuse according to National Institute of Drug Abuse classifications. Descriptive statistics were used to analyze the data collected. Results In 2013, 742 different medications were returned, and 64 (8.63%) were potential drugs of abuse. In the years 2014-2016, 117 (11.43%) returned medications were potential drugs of abuse. In 2017, 40 (13.27%) returned medications were potentially abused drugs. Opioid analgesics were the most common potentially abused medication returned, accounting for 51.6%, 62.4%, and 65% of potentially abused medications returned in 2013, 2014-2016, and 2017, respectively. The other most common potentially abused returned medications were benzodiazepines (10.9%, 12.8%, 7.5%). The return of hypnotic medications increased over the study period from 0% in 2013 to 12.5% of potentially abused medications in 2017. The return of other medications such as loperamide and dextromethorphan varied over the study period. Conclusion The rate of potentially abused medications returned steadily rose over the period of the study. Heightened awareness and increased opportunities for proper disposal including the placement of permanent drug disposal locations may account for the decreased number of prescriptions returned following 2013.

Spatially resolved interference is observed between high-order harmonics generated in two longitudinally separated gas targets. High-contrast modulations in the intensity of each harmonic order up to the cutoff are observed on-axis in the far field of the source as the separation between the gas targets is increased. For low-order harmonics, additional off-axis modulations are observed, which are attributed to the interference between the contributions from the long quantum trajectories from each gas target. The inherent synchronization of this setup offers the prospect for high-stability metrology of quantum states with ultrafast temporal resolutions.

Modified vaccinia virus Ankara (MVA), an attenuated poxvirus, has been developed as a potential vaccine vector for use against cancer and multiple infectious diseases, including human immunodeficiency virus (HIV). MVA is highly immunogenic and elicits strong cellular and humoral responses in preclinical models and humans. However, there is potential to further enhance the immunogenicity of MVA, as MVA-infected cells undergo rapid apoptosis, leading to faster clearance of recombinant antigens and potentially blunting a greater response. Here, we generated MVA-B13R by replacing the fragmented 181R/182R genes of MVA with a functional anti-apoptotic gene, B13R, and confirmed its anti-apoptotic function against chemically induced apoptosis in vitro. In addition, MVA-B13R showed a significant delay in induction of apoptosis in muscle cells derived from mice and humans, as well as in plasmacytoid dendritic cells (pDCs) and CD141(+) DCs from rhesus macaques, compared to the induction of apoptosis in MVA-infected cells. MVA-B13R expressing simian immunodeficiency virus (SIV) Gag and Pol and HIV envelope (SHIV) (MVA-B13R/SHIV) produced higher levels of envelope in the supernatants than MVA/SHIV-infected DF-1 cells in vitro. Immunization of BALB/c mice showed induction of higher levels of envelope-specific antibody-secreting cells and memory B cells, higher IgG antibody titers, and better persistence of antibody titers with MVA-B13R/SHIV than with MVA/SHIV. Gene set enrichment analysis of draining lymph node cells from day 1 after immunization showed negative enrichment for interferon responses in MVA-B13R/SHIV-immunized mice compared to the responses in MVA/SHIV-immunized mice. Taken together, these results demonstrate that restoring B13R functionality in MVA significantly delays MVA-induced apoptosis in muscle and antigen-presenting cells in vitro and augments vaccine-induced humoral immunity in mice. IMPORTANCE MVA is an attractive viral vector for vaccine development due to its safety and immunogenicity in multiple species and humans even under conditions of immunodeficiency. Here, to further improve the immunogenicity of MVA, we developed a novel vector, MVA-B13R, by replacing the fragmented anti-apoptotic genes 181R/182R with a functional version derived from vaccinia virus, B13R. Our results show that MVA-B13R significantly delays apoptosis in antigen-presenting cells and muscle cells in vitro and augments vaccine-induced humoral immunity in mice, leading to the development of a novel vector for vaccine development against infectious diseases and cancer.

High-throughput DNA sequencing enables the study of experimental evolution in near real time. Until now, mutants with deletions of nonessential host range genes were used in experimental evolution of vaccinia virus (VACV). Here, we guided the selection of adaptive mutations that enhanced the fitness of a hybrid virus in which an essential gene had been replaced with an ortholog from another poxvirus genus. Poxviruses encode a complete system for transcription, including RNA polymerase and stage-specific transcription factors. The abilities of orthologous intermediate transcription factors from other poxviruses to substitute for those of VACV, as determined by transfection assays, corresponded with the degree of amino acid identity. VACV in which the A8 or A23 intermediate transcription factor subunit gene was replaced by the myxoma (MYX) virus ortholog exhibited decreased replication. During three parallel serial passages of the hybrid virus with the MYXA8 gene, plaque sizes and virus yields increased. DNA sequencing of virus populations at passage 10 revealed high frequencies of five different single nucleotide mutations in the two largest RNA polymerase subunits, RPO147 and RPO132, and two different Kozak consensus sequence mutations predicted to increase translation of the MYXA8 mRNA. Surprisingly, there were no mutations within either intermediate transcription factor subunit. Based on homology with Saccharomyces cerevisiae RNA polymerase, the VACV mutations were predicted to be buried within the internal structure of the enzyme. By directly introducing single nucleotide substitutions into the genome of the original hybrid virus, we demonstrated that both RNA polymerase and translation-enhancing mutations increased virus replication independently. IMPORTANCE Previous studies demonstrated the experimental evolution of vaccinia virus (VACV) following deletion of a host range gene important for evasion of host immune defenses. We have extended experimental evolution to essential genes that cannot be deleted but could be replaced by a divergent orthologous gene from another poxvirus. Replacement of a VACV transcription factor gene with one from a distantly related poxvirus led to decreased fitness as evidenced by diminished replication. Serially passaging the hybrid virus at a low multiplicity of infection provided conditions for selection of adaptive mutations that improved replication. Notably, these included five independent mutations of the largest and second largest RNA polymerase subunits. This approach should be generally applicable for investigating adaptation to swapping of orthologous genes encoding additional essential proteins of poxviruses as well as other viruses.

An XUV interferometer composed of two inline high harmonic generation regions is used to characterize different ionized electron quantum paths. We unambiguously observe interference between long and short trajectories, revealing their attosecond-scale relative timing.

In this paper we present our plans for an auxiliary OPCPA beamline for the Vulcan PW laser facility. It will be capable of delivering 30J

Trimeric HIV-1 envelope (Env) immunogens are attractive due to their ability to display quaternary epitopes targeted by broadly neutralizing antibodies (bNAbs) while obscuring unfavorable epitopes. Results from the RV144 trial highlighted the importance of vaccine-induced HIV-1 Env V1V2-directed antibodies, with key regions of the V2 loop as targets for vaccine-mediated protection. We recently reported that a trimeric JRFL-gp120 immunogen, generated by inserting an N-terminal trimerization domain in the V1 loop region of a cyclically permuted gp120 (cycP-gp120), induces neutralizing activity against multiple tier-2 HIV-1 isolates in guinea pigs in a DNA prime/protein boost approach. Here, we tested the immunogenicity of cycP-gp120 in a protein prime/boost approach in rabbits and as a booster immunization to DNA/modified vaccinia Ankara (MVA)-vaccinated rabbits and rhesus macaques. In rabbits, two cycP-gp120 protein immunizations induced 100-fold higher titers of high-avidity gp120-specific IgG than two gp120 immunizations, with four total gp120 immunizations being required to induce comparable titers. cycP-gp120 also induced markedly enhanced neutralizing activity against tier-1A and -1B HIV-1 isolates, substantially higher binding and breadth to gp70-V1V2 scaffolds derived from a multiclade panel of global HIV-1 isolates, and antibodies targeting key regions of the V2-loop region associated with reduced risk of infection in RV144. Similarly, boosting MVA- or DNA/MVA-primed rabbits or rhesus macaques with cycP-gp120 showed a robust expansion of gp70-V1V2-specific IgG, neutralization breadth to tier-1B HIV-1 isolates, and antibody-dependent cellular cytotoxicity activity. These results demonstrate that cycP-gp120 serves as a robust HIV Env immunogen that induces broad anti-V1V2 antibodies and promotes neutralization breadth against HIV-1. IMPORTANCE Recent focus in HIV-1 vaccine development has been the design of trimeric HIV-1 Env immunogens that closely resemble native HIV-1 Env, with a major goal being the induction of bNAbs. While the generation of bNAbs is considered a gold standard in vaccine-induced antibody responses, results from the RV144 trial showed that nonneutralizing antibodies directed toward the V1V2 loop of HIV-1 gp120, specifically the V2 loop region, were associated with decreased risk of infection, demonstrating the need for the development of Env immunogens that induce a broad anti-V1V2 antibody response. In this study, we show that a novel trimeric gp120 protein, cycP-gp120, generates high titers of high-avidity and broadly cross-reactive anti-V1V2 antibodies, a result not found in animals immunized with monomeric gp120. These results reveal the potential of cycP-gp120 as a vaccine candidate to induce antibodies associated with reduced risk of HIV-1 infection in humans.

Viruses are used as expression vectors for protein synthesis, immunology research, vaccines, and therapeutics. Advantages of poxvirus vectors include the accommodation of large amounts of heterologous DNA, the presence of a cytoplasmic site of transcription, and high expression levels. On the other hand, competition of approximately 200 viral genes with the target gene for expression and immune recognition may be disadvantageous. We describe a vaccinia virus (VACV) vector that uses an early promoter to express the bacteriophage T7 RNA polymerase; has the A23R intermediate transcription factor gene deleted, thereby restricting virus replication to complementing cells; and has a heterologous gene regulated by a T7 promoter. In noncomplementing cells, viral early gene expression and DNA replication occurred normally but synthesis of intermediate and late proteins was prevented. Nevertheless, the progeny viral DNA provided templates for abundant expression of heterologous genes regulated by a T7 promoter. Selective expression of the Escherichia coli lac repressor gene from an intermediate promoter reduced transcription of the heterologous gene specifically in complementing cells, where large amounts might adversely impact VACV replication. Expression of heterologous proteins mediated by the A23R deletion vector equaled that of a replicating VACV, was higher than that of a nonreplicating modified vaccinia virus Ankara (MVA) vector used for candidate vaccines in vitro and in vivo, and was similarly immunogenic in mice. Unlike the MVA vector, the A23R deletion vector still expresses numerous early genes that can restrict immunogenicity as demonstrated here by the failure of the prototype vector to induce interferon alpha. By deleting immunomodulatory genes, we anticipate further improvements in the system., IMPORTANCE Vaccines provide an efficient and effective way of preventing infectious diseases. Nevertheless, new and better vaccines are needed. Vaccinia virus, which was used successfully as a live vaccine to eradicate smallpox, has been further attenuated and adapted as a recombinant vector for immunization against other pathogens. However, since the initial description of this vector system, only incremental improvements largely related to safety have been implemented. Here we described novel modifications of the platform that increased expression of the heterologous target gene and decreased expression of endogenous vaccinia virus genes while providing safety by preventing replication of the candidate vaccine except in complementing cells used for vector propagation.

Chirped pulses have important applications in [optical parametric] chirped pulse amplification ([OP]CPA), telecommunications, molecular alignment, chirp-assisted sum frequency generation, dispersive Fourier transform spectroscopy and coherent control [1, 2]. Knowledge of the nonlinear dispersion of these pulses is required for accurate extraction of information from experiments, as well as enabling optimal operation of [OP]CPA systems.

The complete characterisation of ultrashort optical pulses is a key capability in the design, optimisation and implementation of any ultrafast laser system or experiment and an accurate means to quantify the complex spectral or temporal amplitude of the field enables the maximum information to be extracted from dynamic measurements.

Modified vaccinia virus Ankara (MVA) is the leading poxvirus vector for development of vaccines against diverse infectious diseases. This distinction is based on high expression of proteins and good immunogenicity despite an inability to assemble infectious progeny in human cells, which together promote efficacy and safety. Nevertheless, the basis for the host-range restriction is unknown despite past systematic attempts to identify the relevant missing viral gene(s). The search for host-range factors is exacerbated by the large number of deletions, truncations and mutations that occurred during the long passage history of MVA in chicken embryo fibroblasts. By whole genome sequencing of a panel of recombinant host-range extended (HRE) MVAs generated by marker rescue with 40 kbp segments of vaccinia virus DNA, we identified serine protease inhibitor 1 (SPI-1) as one of several candidate host-range factors present in those viruses that gained the ability to replicate in human cells. Electron microscopy revealed that the interruption of morphogenesis in human cells infected with MVA occurred at a similar stage as that of a vaccinia virus strain WR SPI-1 deletion mutant. Moreover, the introduction of the SPI-1 gene into the MVA genome led to more than a 2-log enhancement of virus spread in human diploid MRC-5 cells, whereas deletion of the gene diminished the spread of HRE viruses by similar extents. Furthermore, MRC-5 cells stably expressing SPI-1 also enhanced replication of MVA. A role for additional host range genes was suggested by the restoration of MVA replication to a lower level relative to HRE viruses, particularly in other human cell lines. Although multiple sequence alignments revealed genetic changes in addition to SPI-1 common to the HRE MVAs, no evidence for their host-range function was found by analysis thus far. Our finding that SPI-1 is host range factor for MVA should simplify use of high throughput RNAi or CRISPR/Cas single gene methods to identify additional viral and human restriction elements., Author summary Poxvirus vectors have outstanding properties for development of vaccines against a myriad of infectious agents due to their ability to retain long segments of foreign DNA and high-level gene expression. Safety concerns led to a preference for attenuated poxviruses that lost the ability to produce infectious progeny in human cells. The most widely used poxvirus vector is modified vaccinia virus Ankara (MVA), which exhibits an extreme host-range restriction in most mammalian cells. MVA was attenuated by passaging more than 500 times in chicken embryo fibroblasts during which large deletions and numerous additional genetic changes occurred. Despite ongoing clinical testing of MVA-vectored vaccines, the basis for its host-range restriction remained unknown. Here we show that re-introduction of the SPI-1 gene into MVA or host cells increased virus spread by more than 100-fold in a human diploid cell line, providing an important insight into the mechanism responsible for the host-range restriction. This information could help design improved vectors and develop non-avian cell lines for propagation of candidate MVA vaccines.

Korea Astronomy and Space Science Institute (Republic of Korea) [GN-2008A-Q-17, GS-2018A-Q-315]; NSF [AST-1615455, AST-1821987, 1821967, AST-1515559]; NASA grant [ADAP-80NSSC19K0578]; DIRAC Institute in the Department of Astronomy at the University of Washington

We describe the GW follow-up strategy and subsequent results of the DLT40 during the second science run (O2) of the LVC. Depending on the information provided in the GW alert together with the localization map sent by the LVC, DLT40 would respond promptly to image the corresponding galaxies selected by our ranking algorithm in order to search for possible EM counterparts in real time. During the LVC O2 run, DLT40 followed ten GW triggers, observing between $\sim$20-100 galaxies within the GW localization area of each event. From this campaign, we identified two real transient sources within the GW localizations with an appropriate on-source time -- one was an unrelated type Ia supernova (SN~2017cbv), and the other was the optical kilonova, AT 2017fgo/SSS17a/DLT17ck, associated with the binary neutron star coalescence GW170817 (a.k.a gamma-ray burst GRB170817A). We conclude with a discussion of the DLT40 survey's plans for the upcoming LVC O3 run, which include expanding our galaxy search fields out to $D\approx$65 Mpc to match the LVC's planned three-detector sensitivity for binary neutron star mergers., 38 pages, 8 figures and 14 tables, Submitted to ApJ

The topic is a national review of content and clinical experiences in undergraduate pediatric nursing education with recommendations for strengthening the pediatric nursing curriculum. American Association of Colleges of Nursing member programs ( N = 596) were surveyed with 344 schools responding. A 39-item survey collected school demographics, faculty characteristics, pediatric classroom and clinical information, and actual and perceived barriers to implementing the pediatric curriculum. Recommendations for change were offered by participants attending the 2011 Institute of Pediatric Nursing Nursing Forum. A mean of 33 ( SD = 27) total undergraduate faculty included an average of 3.1 ( SD = 3.11) faculty with graduate specialization and/or recent clinical experience in pediatrics. Within a mean of 43 (range = 0–136 hours) pediatric classroom hours, more than 59% of programs reported 2 hours or less in pediatric genetics, environmental health, and child nutrition. Content focused on acute and specialty care with programs using pediatric inpatient medical (68%) and surgical units (40%) for clinical learning. Recruiting pediatric faculty was a common issue and reported as extremely (23%) to moderately difficult (26%). Competition for clinical practice sites (76%) was a reported barrier. Adjustments in the pediatric undergraduate curriculum are recommended to highlight current health issues experienced by children including expansion of clinical learning experiences to settings where children live, learn, and play.

Objective Seizures are common among newborns with hypoxic-ischaemic encephalopathy (HIE) but the relationship between seizure burden and severity of brain injury among neonates receiving therapeutic hypothermia (TH) for HIE is unclear. We tested the hypothesis that seizure burden is associated with cerebral tissue injury independent of amplitude-integrated EEG (aEEG) background activity. Study design Term neonates undergoing 72 h of TH at four centres were selected for study if they had continuous aEEG and MRI. The aEEG with corresponding 2-channel raw EEG (aEEG/EEG), was classified by severity of background and seizure burden; MR images were classified by the severity of tissue injury. Results Of 85 neonates, 52% had seizures on aEEG/ EEG. Overall, 35% had high seizure burden, 49% had abnormal aEEG background in the first 24 h and 36% had severe injury on MRI. Seizures were most common on the first day, with significant recurrence during and after rewarming. Factors associated with severe injury on MRI were high seizure burden, poor aEEG background, 10 min Apgar and the need for more than one anticonvulsant. In multivariate logistic regression, high seizure burden was independently associated with greater injury on MRI (OR 5.00, 95% CI 1.47 to 17.05 p=0.01). Neither aEEG background, nor 10 min Apgar score were significant. Conclusions Electrographic seizure burden is associated with severity of brain injury on MRI in newborns with HIE undergoing TH, independent of degree of abnormality on aEEG background. Seizures are common during cooling, particularly on day 1, with a significant rebound on day 4.

Modified vaccinia virus Ankara (MVA) is being widely investigated as a safe smallpox vaccine and as an expression vector to produce vaccines against other infectious diseases and cancer. MVA was isolated following more than 500 passages in chick embryo fibroblasts and suffered several major deletions and numerous small mutations resulting in replication defects in human and most other mammalian cells as well as severe attenuation of pathogenicity. Due to the host range restriction, primary chick embryo fibroblasts are routinely used for production of MVA-based vaccines. While a replication defect undoubtedly contributes to safety of MVA, it is worth considering whether host range and attenuation are partially separable properties. Marker rescue transfection experiments resulted in the creation of recombinant MVAs with extended mammalian cell host range. Here, we characterize two host-range extended rMVAs and show that they (i) have acquired the ability to stably replicate in Vero cells, which are frequently used as a cell substrate for vaccine manufacture, (ii) are severely attenuated in immunocompetent and immunodeficient mouse strains following intranasal infection, (iii) are more pathogenic than MVA but less pathogenic than the ACAM2000 vaccine strain at high intracranial doses, (iv) do not form lesions upon tail scratch in mice in contrast to ACAM2000 and (v) induce protective humoral and cell-mediated immune responses similar to MVA. The extended host range of rMVAs may be useful for vaccine production.

We report the operation of an optical parametric amplifier (OPA) capable of producing gigawatt peak-power laser pulses with tunable wavelength in either the visible or near-infrared spectrum. The OPA has two distinct operation modes (i) generation of >350 uJ, sub 100 fs pulses, tunable between 1250 - 1550 nm; (ii) generation of >190 uJ, sub 150 fs pulses tunable between 490 - 530 nm. We have recorded high-order harmonic spectra over a wide range of driving wavelengths. This flexible source of femtosecond pulses presents a useful tool for exploring the wavelength-dependence of strong-field phenomena, in both the multi-photon and tunnel ionization regimes., 14 pages, 9 figures, This paper was published in Proceedings of SPIE 10088, Nonlinear Frequency Generation and Conversion: Materials and Devices XVI, doi 10.1117/12.2250775

This unit first describes how to infect cells with vaccinia virus and then transfect them with a plasmid-transfer vector to generate a recombinant virus. Methods are also presented for purifying vaccinia virus and for isolating viral DNA, which can be used during transfection. Also presented are selection and screening methods used to isolate recombinant viruses and a method for the amplification of recombinant viruses. Finally, a method for live immunostaining that has been used primarily for detection of recombinant modified vaccinia virus Ankara (MVA) is presented.