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This paper evaluates risk-oriented frameworks for explaining environmental, social, and economic changes faced by fishing and herding communities in the Turkana Basin during and after the African Humid Period (AHP, 15?5?ka). The orbitally-forced AHP created moist conditions, high lake levels, and unusual hydrological connections across much of northern and eastern Africa. As arid conditions set in and rainfall decreased between 5.3 and 3.9?ka in eastern Africa, Lake Turkana (NW Kenya) shrank dramatically. Shoreline retreat coincided with an expansion of open plains, creating new ecological conditions and potential opportunities for early herders in the basin. In this changing landscape, economies shifted from food procurement (fishing/hunting aquatic resources) to food production (herding), likely through both in-migration by pastoralists and adoption of herding by local fishers. Early pastoralists also built at least seven megalithic pillar sites that served as communal cemeteries during this time. Recent research has shown that local environmental dynamics ? both during and after the AHP ? were complex, demanding a more careful interrogation of the notion that post-AHP life entailed new and/or heightened risks. Risk-buffering strategies might include mobility, diversification, physical storage, and exchange. Archaeologists working around Lake Turkana have proposed that economic shifts from fishing to pastoralism entailed increased mobility as a risk-buffering strategy to deal with aridity and resource unpredictability, and that pillar sites ? as fixed landmarks in an unstable landscape ? provided settings for congregation and exchange amongst increasingly mobile herding communities. However, recent research has shown that local environmental dynamics in the Lake Turkana basin ? both during and after the AHP ? were more complex than previously thought, necessitating re-evaluation of the notion that post-AHP life entailed new and/or heightened risks. Here, we explore risk buffering strategies (e.g. mobility, diversification, physical storage and/or exchange) as only one category of potential explanation for the new social practices observed in the region at this time. Gauging their applicability requires us to (a) assess the spatial mobility of communities and individuals interred at pillar sites; (b) evaluate whether and how mobility strategies may have changed as pastoralism supplanted fishing; and (c) examine alternative explanations for social and economic changes. Introduction Understanding risk in fishinghunting-gathering and pastoral economies - Considering risk in FHG economies - Risk perception and strategic action in pastoral economic contexts - Evaluating relations between mobility, risk, and reliability Climate and ecology records during and after the AHP - Lake sediments - Botanical records - Herbivore isotope records The archaeological record - Fisher-hunter-gatherers around Lake Turkana during the African Humid Period - Middle Holocene aridity and the advent of herding - “Before and after” versus processes of change Discussion: Ways forward - Fisher-hunter-gatherer groups during the African Humid Period - The advent of pastoralism - Mobility Conclusions

Virophagy, the selective autophagosomal engulfment and degradation of viral components, is crucial for antiviral immunity. However, the mechanisms leading to viral antigen recognition and autophagy induction remain poorly understood. Here, we identify a novel kinase, Cyclin-dependent kinase-like 5 (CDKL5), as an essential regulator of virophagy. Deletion of CDKL5 or abrogation of its kinase activity reduced virophagy of Sindbis virus (SINV), a neurotropic RNA virus, and increased intracellular accumulation of SINV capsid proteins and cellular cytotoxicity. Mechanistically, through direct phosphorylation of the selective autophagy receptor p62, CDKL5 promoted formation of p62 inclusion bodies that bound capsid. Loss of CDKL5 disrupted the capsid-p62 interaction, and a p62 phosphomimetic mutant rescued the interaction. CDKL5 knockout mice demonstrated increased neuronal cell death after SINV infection and enhanced lethality after infection with several human viruses. Overall, these findings identify a cell-autonomous innate immune mechanism for autophagy activation to clear toxic viral capsid aggregates during infection.

The ADEO subsystem is a scalable drag augmentation device that uses the residual Earth atmosphere present in Low Earth Orbit (LEO) to passively de-orbit of satellites between 1 and 2000 kg. For the de-orbit maneuvre, a large surface is deployed which multiplies the drag effective surface of the satellite significantly. Thereby the drag force is increased as well causing accelerated decay in orbit altitude. Advantageous about a drag augmentation device is that it does not require any active steering and can be designed for passive attitude stabilization thereby making it applicable for non-operational, tumbling spacecrafts as well. The ADEO subsystem consists of four deployable booms that span four sail segments in a planar shaped configuration. While the sails are made of an aluminum-coated polyimide foil, its coating thickness was chosen such that it provides sufficient protection from the LEO space environment. The current activity commenced in August 2018 is going to provide a fully qualified Protoflight Model (PFM) for a follow-up “In Orbit Demonstration” (IOD) in 2021/2022 (ADEO is selected as payload on the European Commission IOD/IOV satellite programme). In May 2020, the team passed the Manufacturing Readiness Review (MRR). An extensive Breadboarding- and Engineering Model campaign including life tests had already been carried out in 2019. The first ADEO-L PFM consists of a 5 m x 5 m dragsail deployed under control of own onboard electronics. Optionally, ADEO-L systems can be equipped with a so-called “watchdog routine” inside the electronics which is able to recognize the point in time when the satellite has come to the end of its life circle. With the help of an on-board battery the sail will be deployed automatically after a certain time in orbit. Operating like this, ADEO-L can be truly called “100% passive”, a “CleanGreen Space Mission”. First commercial candidate missions to be targeted after the successful EC-IOD mission were already identified by Airbus DS (DE) and QinetiQ (BE).

Enteric viruses encounter various bacteria in the host, which can impact infection outcomes. The interactions between noroviruses and enteric bacteria are not well understood. Previous work determined that murine norovirus (MNV), a model norovirus, had decreased replication in antibiotic-treated mice compared with conventional mice. Although this suggests that the microbiota promotes MNV infection, the mechanisms are not completely understood. Additionally, prior work with other enteric viruses, such as poliovirus and coxsackievirus B3, demonstrated that virions bind bacteria, and exposure to bacteria stabilizes viral particles and limits premature RNA release. Therefore, we examined interactions between MNV and specific bacteria and the consequences of these interactions. We found that the majority of Gram-positive bacteria tested stabilized MNV, while Gram-negative bacteria did not stabilize MNV. Both Gram-positive and Gram-negative bacteria bound to MNV. However, bacterial binding alone was not sufficient for virion stabilization, since Gram-negative bacteria bound MNV but did not stabilize virions. Additionally, we found that bacteria conditioned medium also stabilized MNV and this stabilization may be due to a small heat-stable molecule. Overall, this work identifies specific bacteria and bacterial components that stabilize MNV and may impact virion stability in the environment.

Tracheostomaventile haben sich zur Stimmrehabilitation bei tracheotomierten und laryngektomierten Patienten bewahrt. Dennoch wurde in den letzten Jahren eine Reihe von schwerwiegenden Zwischenfallen mit Tracheostomaventilen publiziert. Die Analyse der Zwischenfalle sowie der auf dem Markt verfugbaren Tracheostomaventile, ihrer Funktionen und Einschrankungen ermoglicht es, typische Risiken abzuleiten. Die meisten gemeldeten Zwischenfalle verursachten das versehentliche Befullen des Cuffs einer Trachealkanule bei aufgesetztem Tracheostomaventil und die Verwechslung eines Tracheostomaventils mit einem HME(„heat and moisture exchanger“)-Filter. Diese Fehler verursachten die komplette Blockade des exspiratorischen Atemweges, und es kam zu einem Barotrauma der Lunge mit Pneumothorax und Asphyxie. Ein weiteres typisches Risiko ist die mangelnde Uberwachung maschinell beatmeter Patienten wahrend der Nutzung des Tracheostomaventils. Eine klare Kennzeichnung von Tracheostomaventilen sowie die Schulung des Personals in Krankenhausern und Pflegeeinrichtungen bezuglich der typischen Risiken von Tracheostomaventilen konnten die assoziierten Gefahren wesentlich reduzieren.

Coxsackieviruses primarily infect the gastrointestinal tract of humans, but they can disseminate systemically and cause severe disease. Using antibiotic treatment regimens to deplete intestinal microbes in mice, several groups have shown that bacteria promote oral infection with a variety of enteric viruses. However, it is unknown whether antibiotics have microbiota-independent antiviral effects for enteric viruses or whether antibiotics influence extra-intestinal, systemic infection. Here, we examined the effects of antibiotics on systemic enteric virus infection by performing intraperitoneal injections of either coxsackievirus B3 (CVB3) or poliovirus followed by quantification of viral titers. We found that antibiotic treatment reduced systemic infection for both viruses. Interestingly, antibiotics reduced CVB3 titers in germ-free mice, suggesting that antibiotic treatment alters CVB3 infection through a microbiota-independent mechanism. Overall, these data provide further evidence that antibiotics can have noncanonical effects on viral infection.

Quantification is no longer a practice of natural science only but has become part of human sciences and everyday life as well. As a direct measurement, which fits the axiomatic of the representational theory of measurement, is mostly infeasible in the social sciences, indicators are used and frequently aggregated to indexes. The index scores can be used to construct a ranking of the units (HDI, PISA). Measurement level and meaning of the data remain often unknown (pseudo-metrical scaling). Furthermore many variables in the field of education are not quantifiable. In the course of globalization and international competition, an indicator system for educational quality measurement (PISA, TIMMS) and goal achievement (Education for All, Millenium Development Goals, Sustainable Development Goals), was established and exerts an increasing impact on national educational systems.The main concerns of indicator-based steering are its methodological limitations and the transformation from a descriptive information base to a normative control system.

Objective:Recent trials provide high-quality evidence for second-line treatment of convulsive status epilepticus (CSE) in children. However, the most effective medications for other seizure emergencies are poorly understood without established treatment algorithms. We investigated children presenting to the emergency department with repetitive or prolonged convulsions who required intravenous long-acting antiseizure medications, to determine the relative importance and treatment responsiveness of status epilepticus and seizure clusters. Methods: Retrospective observational study in the emergency department, Royal Children's Hospital, Melbourne, Australia (annual census 90 000) using hospital electronic medical records data of patients presenting with seizures in 2018. For patients receiving parenteral long-acting antiseizure medications, seizures were categorized as convulsive status epilepticus, nonconvulsive status epilepticus, and seizure clusters. Results: 1468 patients (2% of all visits) presented with seizures to the emergency department in 2018. Long-acting antiseizure medications were administered to 97 (7%) children for the emergency management of seizures. The majority presented with seizure clusters (n = 69; 71%). Only 11 (11%) were in convulsive status epilepticus and 17 (18%) in nonconvulsive status epilepticus. In convulsive status epilepticus, nonconvulsive status epilepticus, and seizure clusters, phenytoin was used in 27%, 53%, and 58% and levetiracetam in 73%, 47%, and 32%, respectively. Conclusions:Convulsive status epilepticus represents a small portion of patients requiring parenteral long-acting antiseizure medications. Seizure clusters accounted for >6 times the number of convulsive status epilepticus, yet evidence and treatment algorithms are lacking.

Enteric viruses encounter various bacteria in the host which can impact infection outcomes. The interactions between noroviruses and enteric bacteria are not well understood. Previous work determined that murine norovirus (MNV), a model norovirus, had decreased replication in antibiotic-treated mice compared with conventional mice. Although this suggests that microbiota promote MNV infection, the mechanisms are not completely understood. Additionally, prior work with other enteric viruses such as poliovirus and coxsackievirus B3 demonstrated that virions bind bacteria, and exposure to bacteria stabilizes viral particles and limits premature RNA release. Therefore, we examined interactions between MNV and specific bacteria and the consequences of these interactions. We found that the majority of Gram-positive bacteria tested stabilized MNV, while Gram-negative bacteria did not stabilize MNV. Both Gram-positive and Gram-negative bacteria bound to MNV. However, bacterial binding alone was not sufficient for virion stabilization since Gram-negative bacteria bound MNV but did not stabilize virions. Additionally, we found that bacterial conditioned media also stabilized MNV and this stabilization may be due to a small heat stable molecule. Overall this work identifies specific bacteria and bacterial components that stabilize MNV and may impact virion stability in the environment.ImportanceEnteric viruses are exposed to a wide variety of bacteria in the intestine, but effects of bacteria on viral particles are incompletely understood. We found that murine norovirus (MNV) virion stability is enhanced in the presence of several Gram-positive bacterial strains. Virion stabilizing activity was also present in bacterial culture medium, and activity was retained upon heat or protease treatment. These results suggest that certain bacteria and bacterial products may promote MNV stability in the environment, which could influence viral transmission.

RNA virus populations are diverse due to a variety of factors, including lack of proofreading of the viral RNA-dependent RNA polymerase. These diverse viral populations include defective viruses incapable of productive infection. Recent studies have determined the existence of several modes of viral transmission outside of canonical pathways, including en bloc transmission of multiple viruses into a single host cell via membrane vesicles. Additionally, it has recently been determined that viral aggregation and bacteria can facilitate the delivery of multiple viruses to a single cell. Co-infection of RNA viruses is important since it has the potential to enhance viral fitness. Furthermore, through complementation and recombination, co-infection could potentially promote “resurrection” of otherwise defective viral genomes and has the potential to expand viral diversity.

RNA viruses exist as genetically heterogeneous populations due to high mutation rates, and many of these mutations reduce fitness and/or replication speed. However, it is unknown whether mutations can increase replication speed of a virus already well adapted to replication in cultured cells. By sequentially passaging coxsackievirus B3 in cultured cells and collecting the very earliest progeny, we selected for increased replication speed. We found that a single mutation in a viral capsid protein, VP1-F106L, was sufficient for the fast-replication phenotype. Characterization of this mutant revealed quicker genome release during entry compared to wild-type virus, highlighting a previously unappreciated infection barrier. However, this mutation also reduced capsid stability in vitro and reduced replication and pathogenesis in mice. These results reveal a tradeoff between overall replication speed and fitness. Importantly, this approach-selecting for the earliest viral progeny-could be applied to a variety of viral systems and has the potential to reveal unanticipated inefficiencies in viral replication cycles.

BackgroundParamedics are frequently called to attend seizures in children. High-quality evidence on second-line treatment of benzodiazepine (BZD)-refractory convulsions with parenteral long-acting antiepileptic drugs in children has become available from the ED. In order to address the potential need for an alternative agent, we set out to determine the association of BZD use prehospital and the need for respiratory support.MethodsWe conducted a retrospective observational study of state-wide ambulance service data (Ambulance Victoria in Victoria, Australia, population: 6.5 million). Children aged 0–17 years assessed for seizures by paramedics were analysed for demographics, process factors, treatment and airway management. We calculated adjusted ORs (AOR) of the requirement for respiratory support in relation to the number of BZD doses administered.ResultsParamedics attended 5112 children with suspected seizures over 1 year (1 July 2018 to 30 June 2019). Overall, need for respiratory support was low (n=166; 3.2%). Before ambulance arrival, 509 (10.0%) had already received a BZD and 420 (8.2%) were treated with midazolam by paramedics. Of the 846 (16.5%) patients treated with BZD, 597 (70.6%) received 1 BZD dose, 156 (18.4%) 2 doses and 93 (11.0%) >2 doses of BZD. Patients who were administered 1, 2 and >2 doses of BZD received respiratory support in 8.9%, 32.1% (AOR 4.6 vs 1 dose, 95% CI 2.9 to 7.4) and 49.5% (AOR 10.3 vs 1 dose, 95% CI 6.0 to 17.9), respectively.ConclusionsIncreasing administration of BZD doses was associated with higher use of respiratory support. Alternative prehospital antiepileptic drugs to minimise respiratory depression should be investigated in future research.

Animals have evolved unique repertoires of innate immune genes and pathways that provide their first line of defense against pathogens. To reconstruct the ancestry of animal innate immunity, we have developed the choanoflagellate Monosiga brevicollis, one of the closest living relatives of animals, as a model for studying mechanisms underlying pathogen recognition and immune response. We found that M. brevicollis is killed by exposure to Pseudomonas aeruginosa bacteria. Moreover, M. brevicollis expresses STING, which, in animals, activates innate immune pathways in response to cyclic dinucleotides during pathogen sensing. M. brevicollis STING increases the susceptibility of M. brevicollis to P. aeruginosa-induced cell death and is required for responding to the cyclic dinucleotide 2’3’ cGAMP. Furthermore, similar to animals, autophagic signaling in M. brevicollis is induced by 2’3’ cGAMP in a STING-dependent manner. This study provides evidence for a pre-animal role for STING in antibacterial immunity and establishes M. brevicollis as a model system for the study of immune responses.

Autophagy, a process of degradation that occurs via the lysosomal pathway, has an essential role in multiple aspects of immunity, including immune system development, regulation of innate and adaptive immune and inflammatory responses, selective degradation of intracellular microorganisms, and host protection against infectious diseases1,2. Autophagy is known to be induced by stimuli such as nutrient deprivation and suppression of mTOR, but little is known about how autophagosomal biogenesis is initiated in mammalian cells in response to viral infection. Here, using genome-wide short interfering RNA screens, we find that the endosomal protein sorting nexin 5 (SNX5)3,4 is essential for virus-induced, but not for basal, stress- or endosome-induced, autophagy. We show that SNX5 deletion increases cellular susceptibility to viral infection in vitro, and that Snx5 knockout in mice enhances lethality after infection with several human viruses. Mechanistically, SNX5 interacts with beclin 1 and ATG14-containing class III phosphatidylinositol-3-kinase (PI3KC3) complex 1 (PI3KC3-C1), increases the lipid kinase activity of purified PI3KC3-C1, and is required for endosomal generation of phosphatidylinositol-3-phosphate (PtdIns(3)P) and recruitment of the PtdIns(3)P-binding protein WIPI2 to virion-containing endosomes. These findings identify a context- and organelle-specific mechanism-SNX5-dependent PI3KC3-C1 activation at endosomes-for initiation of autophagy during viral infection.

Enteric viruses are important human pathogens that pose a significant global health problem. These viruses infect the gastrointestinal tract, which contains a community of microbes called the 'microbiota'. We and others have shown that intestinal microbiota are crucial for the replication, pathogenesis, and transmission of a variety of enteric viruses. However, the mechanisms underlying microbiota enhancement of enteric virus infection remain unclear. Interestingly, the host immune system is dependent on both the abundance and composition of the intestinal microbiota. Here we review several aspects of how microbiota influence the immune system and how this could potentially impact enteric virus infection.

Tracheostoma valves have proven to be very effective for voice restoration in patients with a tracheotomy or laryngectomy. Nevertheless, in recent years there have been a number of reports about life-threatening incidents with tracheostoma valves. An analysis of these incidents and the commercially available tracheostoma valves, their functions and limitations enables typical risk situations to be derived. The most reported incidents were caused by inadvertently filling the cuff of the tracheostomy tube while the tracheostoma valve was in place and by confusing a heat and moisture exchanger (HME) filter with a tracheostoma valve. These mistakes caused a complete obstruction of the expiratory airway leading to a barotrauma of the lungs with pneumothorax and asphyxia. Another typical risk in mechanically ventilated patients is insufficient monitoring during the use of the tracheostoma valve. Clear marking of tracheostoma valves and a specific training of hospital personnel with respect to the typical risks of tracheostoma valves could effectively reduce the associated dangers.Tracheostomaventile haben sich zur Stimmrehabilitation bei tracheotomierten und laryngektomierten Patienten bewährt. Dennoch wurde in den letzten Jahren eine Reihe von schwerwiegenden Zwischenfällen mit Tracheostomaventilen publiziert. Die Analyse der Zwischenfälle sowie der auf dem Markt verfügbaren Tracheostomaventile, ihrer Funktionen und Einschränkungen ermöglicht es, typische Risiken abzuleiten. Die meisten gemeldeten Zwischenfälle verursachten das versehentliche Befüllen des Cuffs einer Trachealkanüle bei aufgesetztem Tracheostomaventil und die Verwechslung eines Tracheostomaventils mit einem HME(„heat and moisture exchanger“)-Filter. Diese Fehler verursachten die komplette Blockade des exspiratorischen Atemweges, und es kam zu einem Barotrauma der Lunge mit Pneumothorax und Asphyxie. Ein weiteres typisches Risiko ist die mangelnde Überwachung maschinell beatmeter Patienten während der Nutzung des Tracheostomaventils. Eine klare Kennzeichnung von Tracheostomaventilen sowie die Schulung des Personals in Krankenhäusern und Pflegeeinrichtungen bezüglich der typischen Risiken von Tracheostomaventilen könnten die assoziierten Gefahren wesentlich reduzieren.

Production of certified reference materials in support of domestic nuclear forensics programs require volatile precursors for introduction into electromagnetic isotopic separation instruments. β-Diketone chelates of tetravalent actinides are known for their high volatility, but previously developed synthetic approaches require starting material (NpCl4) that is prohibitively difficult and hazardous to prepare. An alternative strategy was developed here that uses controlled potential electrolysis to reduce neptunium to the tetravalent state in submolar concentrations of hydrochloric acid. Four different β-diketone ligands of varying degrees of fluorination were reacted with an aqueous solution of Np4+. Products of this reaction were characterized via X-ray diffraction and infrared spectroscopy, and were found to be neutral 8-coordinate complexes that adopt square antiprismatic crystal geometry. Synthesis of Np β-diketonates by this approach circumvents the necessity of using NpCl4 in tetravalent Np coordination compound synthesis. The volatility of the complexes was assessed using thermogravimetric analysis, where the temperature of sublimation was determined to be in the range of 180° to 205 °C. The extent of fluorination did not appreciably alter the sublimation temperature of the complex. Thermal decomposition of these compounds was not observed during sublimation. High volatility and thermal stability of Np β-diketonates make them ideal candidates for gaseous introduction into isotopic separation instruments.

We present the fabrication and characterization of inter-layer single-mode light-guiding structures in a newly developed photo-structurable polymer via femtosecond laser writing. A host-guest polymer system utilizing external diffusion induces permanent and high refractive index modulation. Analyzing the complete curing and the impact of external diffusion on refractive index profile helps optimize the fabrication process. The fabrications of 4 × 2 array interconnect and 3-waveguide core fan-out device involve only a single layer, and need no stacking or alignment effort. The resulting pitch size and crosstalk between single-mode waveguides are 25 μm and −34 dB, respectively. Adding sensitizer into the photopolymer to increase its sensitivity in two-photon polymerization at a writing wavelength of 390 nm reduces the surface roughness of written structures by a factor of seven.

Coxsackieviruses primarily infect the gastrointestinal tract of humans, but they can disseminate systemically and cause severe disease. Using antibiotic treatment regimens to deplete intestinal microbes in mice, several groups have shown that bacteria promote oral infection with a variety of enteric viruses. However, it is unknown whether antibiotics have microbiota-independent antiviral effects for enteric viruses or whether antibiotics influence extra-intestinal, systemic infection. Here, we examined the effects of antibiotics on systemic enteric virus infection by performing intraperitoneal injections of either coxsackievirus B3 (CVB3) or poliovirus followed by quantification of viral titers. We found that antibiotic treatment reduced systemic infection for both viruses. Interestingly, antibiotics reduced CVB3 titers in germ-free mice, suggesting that antibiotic treatment alters CVB3 infection through a microbiota-independent mechanism. Overall, these data provide further evidence that antibiotics can have noncanonical effects on viral infection.

Bestimmte Viren sind in der Lage, die unterstutzende Rolle von Darmbakterien in Saugetieren zu ubernehmen. Viren mussen also nicht immer gefahrlich sein – sie konnten sogar die Gesundheit ihres Wirts fordern.

Enteric viruses infect the gastrointestinal tract and bacteria can promote replication and transmission of several enteric viruses. Viruses can be inactivated by exposure to heat or bleach, but poliovirus, coxsackievirus B3, and reovirus can be stabilized by bacteria or bacterial polysaccharides, limiting inactivation and aiding transmission. We previously demonstrated that certain N-acetylglucosamine (GlcNAc)-containing polysaccharides can stabilize poliovirus. However, the detailed virus-glycan binding specificity and glycan chain length requirements, and thus the mechanism of virion stabilization, has been unclear. A previous limitation was our lack of defined-length glycans to probe mechanisms and consequences of virus-glycan interactions. Here, we generated a panel of polysaccharides and oligosaccharides to determine the properties required for binding and stabilization of poliovirus. Poliovirus virions are non-enveloped icosahedral 30 nm particles with 60 copies of each of four capsid proteins, VP1-4. VP1 surrounds the fivefold axis and our past work indicates that this region likely contains the glycan binding site. We found that relatively short GlcNAc oligosaccharides, such as a six unit GlcNAc oligomer, can bind poliovirus but fail to enhance virion stability. Virion stabilization required binding of long GlcNAc polymers of greater than 20 units. Our data suggest a model where GlcNAc polymers greater than 20 units bind and bridge adjacent fivefold axes, thus aiding capsid rigidity and stability. This study provides a deeper understanding of enteric virus-bacterial glycan interactions, which is important for virion environmental stability and transmission.ImportanceEnteric viruses are transmitted through the fecal-oral route, but how enteric viruses survive in the environment is unclear. Previously, we found that bacterial polysaccharides enhance poliovirus stability against heat or bleach inactivation, but the specific molecular requirements have been unknown. Here we showed that certain short chain oligosaccharides can bind to poliovirus but do not increase virion stability. Long chain polysaccharides bind and may bridge adjacent sites on the viral surface, thus increasing capsid rigidity and stability. This work defines the unique interactions of poliovirus and glycans, which provides insight into virion environmental stability and transmission.

In the context of the Third International Conference on Humanistic Discourse, this text introduces Douglas J. Osler’s "Images of Legal Humanism"., Dans le cadre du troisième congrès international sur le discours humaniste, le texte propose une introduction à « Images of Legal Humanism » de Douglas J. Osler.

With a half-life of 3.85(5) d, the fission product $^{127}\mathrm{Sb}$ is potentially useful for the characterization of fallout debris that would be collected for forensic analysis following a hypothetical nuclear event. The $\ensuremath{\beta}$ decay of $^{127}\mathrm{Sb}$ has many characteristic $\ensuremath{\gamma}$-ray lines, however, the majority of decay strength is concentrated in the three strongest lines near 686, 473, and 784 keV, based on low-precision spectroscopic measurements from decades ago. In a new measurement of $^{127}\mathrm{Sb}\phantom{\rule{4pt}{0ex}}\ensuremath{\beta}$ decay, obtained from radiochemical separations of U photofission products, we show that the energies of the 686 and 784 lines are actually shifted lower by 0.8 and 1.1 keV, respectively. Such large discrepancies in the nuclear data inhibit accurate isotopic analyses and have important implications, for example, on the assessment of fission debris that might be collected in the days following a nuclear event. Therefore, a new evaluation of $^{127}\mathrm{Sb}\phantom{\rule{4pt}{0ex}}\ensuremath{\beta}$ decay and appropriate revisions to the various nuclear databases are warranted. This paper reports a new set of $\ensuremath{\gamma}$-ray energies and relative intensities corresponding to $^{127}\mathrm{Sb}$ decay.

Dear Colleagues,The UT Southwestern community continues to mourn the loss of Dr. Beth Levine – a renowned physician-scientist, dedicated and caring educator, mentor, respected colleague and friend....

Key message Coordinated association and linkage mapping identified 25 grain quality QTLs in multiple environments, and fine mapping of the Wx locus supports the use of high-density genetic markers in linkage mapping. Abstract There is a wide range of end-use products made from cereal grains, and these products often demand different grain characteristics. Fortunately, cereal crop species including sorghum [Sorghum bicolor (L.) Moench] contain high phenotypic variation for traits influencing grain quality. Identifying genetic variants underlying this phenotypic variation allows plant breeders to develop genotypes with grain attributes optimized for their intended usage. Multiple sorghum mapping populations were rigorously phenotyped across two environments (SC Coastal Plain and Central TX) in 2 years for five major grain quality traits: amylose, starch, crude protein, crude fat, and gross energy. Coordinated association and linkage mapping revealed several robust QTLs that make prime targets to improve grain quality for food, feed, and fuel products. Although the amylose QTL interval spanned many megabases, the marker with greatest significance was located just 12 kb from waxy (Wx), the primary gene regulating amylose production in cereal grains. This suggests higher resolution mapping in recombinant inbred line (RIL) populations can be obtained when genotyped at a high marker density. The major QTL for crude fat content, identified in both a RIL population and grain sorghum diversity panel, encompassed the DGAT1 locus, a critical gene involved in maize lipid biosynthesis. Another QTL on chromosome 1 was consistently mapped in both RIL populations for multiple grain quality traits including starch, crude protein, and gross energy. Collectively, these genetic regions offer excellent opportunities to manipulate grain composition and set up future studies for gene validation. Electronic supplementary material The online version of this article (doi:10.1007/s00122-016-2844-6) contains supplementary material, which is available to authorized users.

// Amanda R. Oran 1 , Clare M. Adams 1 , Xiao-yong Zhang 1 , Victoria J. Gennaro 1 , Harla K. Pfeiffer 1 , Hestia S. Mellert 2 , Hans E. Seidel 3 , Kirsten Mascioli 1 , Jordan Kaplan 1 , Mahmoud R. Gaballa 1 , Chen Shen 4,5 , Isidore Rigoutsos 1 , Michael P. King 6 , Justin L. Cotney 7 , Jamie J. Arnold 8 , Suresh D. Sharma 8 , Ubaldo E. Martinez-Outschoorn 1 , Christopher R. Vakoc 4 , Lewis A. Chodosh 3 , James E. Thompson 9 , James E. Bradner 10 , Craig E. Cameron 8 , Gerald S. Shadel 11,12 , Christine M. Eischen 1 and Steven B. McMahon 1 1 Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA 2 Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, PA, USA 3 Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA 4 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA 5 Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY, USA 6 Department of Biochemistry, Thomas Jefferson University, Philadelphia, PA, USA 7 Genetics and Genome Sciences, University of Connecticut Health, Farmington, CT, USA 8 Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, PA, USA 9 Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA 10 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA,USA 11 Department of Pathology, Yale School of Medicine, New Haven, CT, USA 12 Department of Genetics, Yale School of Medicine, New Haven, CT, USA Correspondence to: Steven B. McMahon, email: // Keywords : MYC, mitochondria, mitochondrial gene expression, tigecycline, synthetic lethality Received : June 08, 2016 Accepted : August 25, 2016 Published : August 31, 2016 Abstract Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production. Fortuitously, MYC-dependent tumor cell death can be induced by inhibiting the mitochondrial gene expression pathway using a variety of strategies, including treatment with FDA-approved antibiotics. In vivo studies using a mouse model of Burkitt’s Lymphoma provide pre-clinical evidence that these antibiotics can successfully block progression of MYC-dependent tumors.

Prevention of type 2 diabetes (T2D) is a great challenge worldwide. The aim of this evidence synthesis was to summarize the available evidence in order to update the European Association for the Study of Diabetes (EASD) clinical practice guidelines for nutrition therapy. We conducted a systematic review and, where appropriate, meta-analyses of randomized controlled trials (RCTs) carried out in people with impaired glucose tolerance (IGT) (six studies) or dysmetabolism (one study) to answer the following questions: What is the evidence that T2D is preventable by lifestyle changes? What is the optimal diet (with a particular focus on diet quality) for prevention, and does the prevention of T2D result in a lower risk of late complications of T2D? The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was applied to assess the certainty of the trial evidence. Altogether seven RCTs (N = 4090) fulfilled the eligibility criteria and were included in the meta-analysis. The diagnosis of incident diabetes was based on an oral glucose tolerance test (OGTT). The overall risk reduction of T2D by the lifestyle interventions was 0.53 (95% CI 0.41; 0.67). Most of the trials aimed to reduce weight, increase physical activity, and apply a diet relatively low in saturated fat and high in fiber. The PREDIMED trial that did not meet eligibility criteria for inclusion in the meta-analysis was used in the final assessment of diet quality. We conclude that T2D is preventable by changing lifestyle and the risk reduction is sustained for many years after the active intervention (high certainty of evidence). Healthy dietary changes based on the current recommendations and the Mediterranean dietary pattern can be recommended for the long-term prevention of diabetes. There is limited or insufficient data to show that prevention of T2D by lifestyle changes results in a lower risk of cardiovascular and microvascular complications. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Coxsackievirus typically infects humans via the gastrointestinal tract, which has a large number of microorganisms collectively referred to as the microbiota. To study how the intestinal microbiota influence enteric virus infection, several groups have used an antibiotic regimen in mice to deplete bacteria. These studies have shown that bacteria promote infection with several enteric viruses. However, very little is known about whether antibiotics influence viruses in a microbiota-independent manner. Here, we sought to determine the effects of antibiotics on coxsackievirus B3 (CVB3) using anin vitrocell culture model in the absence of bacteria. We determined that an aminoglycoside antibiotic, neomycin, enhanced plaque size of CVB3-Nancy strain. Neomycin treatment did not alter viral attachment, translation, or replication. However, we found that the positive charge of neomycin and other positively charged compounds enhanced viral diffusion by overcoming the negative inhibitory effect of sulfated polysaccharides present in agar overlays. Overall, these data lend further evidence that antibiotics can play non-canonical roles in viral infections and that this should be considered when studying enteric virus-microbiota interactions.ImportanceCoxsackieviruses primarily infect the gastrointestinal tract of humans, but they can disseminate systemically and cause severe disease. Using antibiotic treatment regimens to deplete intestinal microbes in mice, several groups have shown the bacteria promote infection with a variety of enteric viruses. However, it is possible that antibiotics have microbiota-independent effects on viruses. Here, we show that an aminoglycoside antibiotic, neomycin, can influence quantification of coxsackievirus in cultured cells in absence of bacteria.

Several viruses encounter various bacterial species within the host and in the environment. Despite these close encounters, the effects of bacteria on picornaviruses specifically is not completely understood. Previous work determined that poliovirus (PV), an enteric virus, has enhanced virion stability when exposed to bacteria or bacterial surface polysaccharides such as lipopolysaccharide. Virion stabilization by bacteria may be important for inter-host transmission since a mutant PV with reduced bacterial binding had a fecal-oral transmission defect in mice. Therefore, we investigated whether bacteria broadly enhance stability of picornaviruses from three different genera: Enterovirus (PV and coxsackievirus B3 (CVB3)), Kobuvirus (Aichi virus) and Cardiovirus (Mengo virus). Furthermore, to delineate strain-specific effects, we examined two strains of CVB3 and a PV mutant with enhanced thermal stability. We determined that specific bacterial strains enhance thermal stability of PV and CVB3, while Mengo virus and Aichi virus are stable at high temperatures in the absence of bacteria. Additionally, we determined that bacteria or lipopolysaccharide can stabilize PV, CVB3, Aichi virus, and Mengo virus during exposure to bleach. These effects are likely mediated through direct interactions with bacteria since viruses bound to bacteria in a pull-down assay. Overall, this work reveals shared and distinct effects of bacteria on a panel of picornaviruses.IMPORTANCERecent studies have shown that bacteria promote infection and stabilization of poliovirus particles, but the breadth of these effects on other members of the Picornaviridae family is unknown. Here, we compared the effect of bacteria on four distinct members of the Picornaviridae family. We found that bacteria reduced inactivation of all of the viruses during bleach treatment, but not all viral strains were stabilized by bacteria during heat treatment. Overall, our data provide insight into how bacteria play differential roles on picornavirus stability.

Enteric viruses, including poliovirus, are spread by the fecal-oral route. In order to persist and transmit to a new host, enteric virus particles must remain stable once they are in the environment. Environmental stressors such as heat and disinfectants can inactivate virus particles and prevent viral transmission. It has been previously demonstrated that bacteria or bacterial surface glycans can enhance poliovirus virion stability and limit inactivation from heat or bleach. While investigating the mechanisms underlying bacterial-enhanced virion thermal stability, we identified and characterized a poliovirus mutant with increased resistance to heat inactivation. This poliovirus mutant, M132V, harbors a single amino acid change in the VP1 capsid-coding that is sufficient to confer heat resistance. M132V was comparable to wild-type virus for replicationin vitro, as well as for replication and pathogenesis in orally-inoculated mice. Although the M132V virus was stable in the absence of bacteria or feces at most temperatures, M132V virus was stabilized by feces at very high temperatures. Additionally, the M132V virus does not have enhanced stability during bleach treatment, suggesting that thermal and bleach inactivation mechanisms are separable. Our results suggest that different mechanisms underlie virion stabilization by bacteria and the M132V mutation. Overall, this work sheds light on factors that influence virion stability.IMPORTANCEViruses spread by the fecal-oral route need to maintain viability in the environment to ensure transmission. Previous work indicated that bacteria and bacterial surface polysaccharides can stabilize viral particles and enhance transmission. To explore factors that influence viral particle stability, we isolated a mutant poliovirus that is heat resistant. This mutant virus does not require feces for stability at most temperatures, but can be stabilized by feces at very high temperatures. Even though the mutant virus is heat resistant, it is susceptible to inactivation by treatment with bleach. This work provides insight into how viral particles maintain infectivity in the environment.

Enteric viruses, including poliovirus, are spread by the fecal-oral route. In order to persist and transmit to a new host, enteric virus particles must remain stable once they are in the environment. Environmental stressors such as heat and disinfectants can inactivate virus particles and prevent viral transmission. It has been previously demonstrated that bacteria or bacterial surface glycans can enhance poliovirus virion stability and limit inactivation from heat or bleach. While investigating the mechanisms underlying bacterially enhanced virion thermal stability, we identified and characterized a poliovirus (PV) mutant with increased resistance to heat inactivation. The M132V mutant harbors a single amino acid change in the VP1 capsid coding that is sufficient to confer heat resistance but not bleach resistance. Although the M132V virus was stable in the absence of bacteria or feces at most temperatures, M132V virus was stabilized by feces at very high temperatures. M132V PV had reduced specific infectivity and RNA uncoating compared with those of wild-type (WT) PV, but viral yields in HeLa cells were similar. In orally inoculated mice, M132V had a slight fitness cost since fecal titers were lower and 12.5% of fecal viruses reverted to the WT. Overall, this work sheds light on factors that influence virion stability and fitness. IMPORTANCE Viruses spread by the fecal-oral route need to maintain viability in the environment to ensure transmission. Previous work indicated that bacteria and bacterial surface polysaccharides can stabilize viral particles and enhance transmission. To explore factors that influence viral particle stability, we isolated a mutant poliovirus that is heat resistant. This mutant virus does not require feces for stability at most temperatures but can be stabilized by feces at very high temperatures. Even though the mutant virus is heat resistant, it is susceptible to inactivation by treatment with bleach. This work provides insight into how viral particles maintain infectivity in the environment.