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While stellar processes are believed to be the main source of feedback in dwarf galaxies, the accumulating discoveries of active galactic nuclei (AGN) in dwarf galaxies over recent years arouse the interest to also consider AGN feedback in them. Fast, AGN-driven outflows, a major mechanism of AGN feedback, have indeed been discovered in dwarf galaxies and may be powerful enough to provide feedback to their dwarf hosts. In this paper, we search for outflows traced by the blueshifted ultraviolet absorption features in three dwarf galaxies with AGN from the sample examined in our previous ground-based study. We confirm outflows traced by blueshifted absorption features in two objects and tentatively detect an outflow in the third object. In one object where the outflow is clearly detected in multiple species, photoionization modeling suggests that this outflow is located ∼0.5 kpc from the AGN, implying a galactic-scale impact. This outflow is much faster and possesses a higher kinetic energy outflow rate than starburst-driven outflows in sources with similar star formation rates, and is likely energetic enough to provide negative feedback to its host galaxy as predicted by simulations. Much broader (∼4000 km s ^−1 ) absorption features are also discovered in this object, which may have the same origin as that of broad absorption lines in quasars. Additionally, strong He ii λ 1640 emission is detected in both objects where the transition falls in the wavelength coverage and is consistent with an AGN origin. In one of these two objects, a blueshifted He ii λ 1640 emission line is clearly detected, likely tracing a highly ionized AGN wind.

We present new JWST NIRSpec integral field spectroscopy (IFS) data for the luminous infrared galaxy NGC 7469, a nearby (70.6 Mpc) active galaxy with a Seyfert 1.5 nucleus that drives a highly ionized gas outflow and a prominent nuclear star-forming ring. Using the superb sensitivity and high spatial resolution of the JWST instrument NIRSpec IFS, we investigate the role of the Seyfert nucleus in the excitation and dynamics of the circumnuclear gas. Our analysis focuses on the [Fe ii ], H _2 , and hydrogen recombination lines that trace the radiation/shocked-excited molecular and ionized interstellar medium around the active galactic nucleus (AGN). We investigate gas excitation through H _2 /Br γ and [Fe ii ]/Pa β emission line ratios and find that photoionization by the AGN dominates within the central 300 pc of the galaxy except in a small region that shows signatures of shock-heated gas; these shock-heated regions are likely associated with a compact radio jet. In addition, the velocity field and velocity dispersion maps reveal complex gas kinematics. Rotation is the dominant feature, but we also identify noncircular motions consistent with gas inflows as traced by the velocity residuals and the spiral pattern in the Pa α velocity dispersion map. The inflow is 2 orders of magnitude higher than the AGN accretion rate. The compact nuclear radio jet has enough power to drive the highly ionized outflow. This scenario suggests that the inflow and outflow are in a self-regulating feeding–feedback process, with a contribution from the radio jet helping to drive the outflow.

We present James Webb Space Telescope (JWST) Near Infrared Spectrograph (NIRSpec) integral field spectroscopy of the nearby luminous infrared galaxy NGC 7469. We take advantage of the high spatial/spectral resolution and wavelength coverage of JWST/NIRSpec to study the 3.3 μ m neutral polycyclic aromatic hydrocarbon (PAH) grain emission on ∼200 pc scales. A clear change in the average grain properties between the star-forming ring and the central AGN is found. Regions in the vicinity of the AGN, with [Ne iii ]/[Ne ii ] > 0.25, tend to have larger grain sizes and lower aliphatic-to-aromatic (3.4/3.3) ratios, indicating that smaller grains are preferentially removed by photodestruction in the vicinity of the AGN. PAH emission at the nucleus is weak and shows a low 11.3/3.3 PAH ratio. We find an overall suppression of the total PAH emission relative to the ionized gas in the central 1 kpc region of the AGN in NGC 7469 compared to what has been observed with Spitzer on 3 kpc scales. However, the fractional 3.3 μ m–to–total PAH power is enhanced in the starburst ring, possibly due to a variety of physical effects on subkiloparsec scales, including recurrent fluorescence of small grains or multiple photon absorption by large grains. Finally, the IFU data show that while the 3.3 μ m PAH-derived star formation rate (SFR) in the ring is 27% higher than that inferred from the [Ne ii ] and [Ne iii ] emission lines, the integrated SFR derived from the 3.3 μ m feature would be underestimated by a factor of 2 due to the deficit of PAHs around the AGN, as might occur if a composite system like NGC 7469 were to be observed at high redshift.

We present James Webb Space Telescope (JWST) imaging of NGC 7469 with the Near-Infrared Camera and the Mid-InfraRed Instrument. NGC 7469 is a nearby, z = 0.01627, luminous infrared galaxy that hosts both a Seyfert Type-1.5 nucleus and a circumnuclear starburst ring with a radius of ∼0.5 kpc. The new near-infrared (NIR) JWST imaging reveals 66 star-forming regions, 37 of which were not detected by Hubble Space Telescope (HST) observations. Twenty-eight of the 37 sources have very red NIR colors that indicate obscurations up to A _v ∼ 7 and a contribution of at least 25% from hot dust emission to the 4.4 μ m band. Their NIR colors are also consistent with young (

We present the results of a James Webb Space Telescope NIRCam investigation into the young massive star cluster (YMC) population in the luminous infrared galaxy VV 114. We identify 374 compact YMC candidates with signal-to-noise ratios ≥ 3, 5, and 5 at F150W, F200W, and F356W, respectively. A direct comparison with our HST cluster catalog reveals that ∼20% of these sources are undetected at optical wavelengths. Based on yggdrasil stellar population models, we identify 17 YMC candidates in our JWST imaging alone with F150W – F200W and F200W – F356W colors suggesting they are all very young, dusty ( A _V = 5–15), and massive (10 ^5.8 < M _⊙ < 10 ^6.1 ). The discovery of these “hidden” sources, many of which are found in the “overlap” region between the two nuclei, quadruples the number of t < 3 Myr clusters and nearly doubles the number of t < 6 Myr clusters detected in VV 114. Now extending the cluster age distribution ( ${dN}/d\tau \propto {\tau }^{\gamma }$ ) to the youngest ages, we find a slope of γ = −1.30 ± 0.39 for 10 ^6 < τ (yr) < 10 ^7 , which is consistent with the previously determined value from 10 ^7 < τ (yr) < 10 ^8.5 , and confirms that VV 114 has a steep age distribution slope for all massive star clusters across the entire range of cluster ages observed. Finally, the consistency between our JWST- and HST-derived age distribution slopes indicates that the balance between cluster formation and destruction has not been significantly altered in VV 114 over the last 0.5 Gyr.

Feedback likely plays a crucial role in resolving discrepancies between observations and theoretical predictions of dwarf galaxy properties. Stellar feedback was once believed to be sufficient to explain these discrepancies, but it has thus far failed to fully reconcile theory and observations. The recent discovery of energetic galaxy-wide outflows in dwarf galaxies hosting active galactic nuclei (AGNs) suggests that AGN feedback may have a larger role in the evolution of dwarf galaxies than previously suspected. In order to assess the relative importance of stellar versus AGN feedback in these galaxies, we perform a detailed Keck/KCWI optical integral field spectroscopic study of a sample of low-redshift star-forming (SF) dwarf galaxies that show outflows in ionized gas in their Sloan Digital Sky Survey spectra. We characterize the outflows and compare them to observations of AGN-driven outflows in dwarfs. We find that SF dwarfs have outflow components that have comparable widths ( W _80 ) to those of outflows in AGN dwarfs, but are much less blueshifted, indicating that SF dwarfs have significantly slower outflows than their AGN counterparts. Outflows in SF dwarfs are spatially resolved and significantly more extended than those in AGN dwarfs. The mass-loss, momentum, and energy rates of star-formation-driven outflows are much lower than those of AGN-driven outflows. Our results indicate that AGN feedback in the form of gas outflows may play an important role in dwarf galaxies and should be considered along with SF feedback in models of dwarf galaxy evolution.

We combine our dynamical modeling black-hole mass measurements from the Lick AGN Monitoring Project 2016 sample with measured cross-correlation time lags and line widths to recover individual scale factors, f , used in traditional reverberation-mapping analyses. We extend our sample by including prior results from Code for AGN Reverberation and Modeling of Emission Lines ( caramel ) studies that have utilized our methods. Aiming to improve the precision of black-hole mass estimates, as well as uncover any regularities in the behavior of the broad-line region (BLR), we search for correlations between f and other AGN/BLR parameters. We find (i) evidence for a correlation between the virial coefficient ${\mathrm{log}}_{10}({f}_{\mathrm{mean},\sigma })$ and black-hole mass, (ii) marginal evidence for a similar correlation between ${\mathrm{log}}_{10}({f}_{\mathrm{rms},\sigma })$ and black-hole mass, (iii) marginal evidence for an anticorrelation of BLR disk thickness with ${\mathrm{log}}_{10}({f}_{\mathrm{mean},\mathrm{FWHM}})$ and ${\mathrm{log}}_{10}({f}_{\mathrm{rms},\mathrm{FWHM}})$ , and (iv) marginal evidence for an anticorrelation of inclination angle with ${\mathrm{log}}_{10}({f}_{\mathrm{mean},\mathrm{FWHM}})$ , ${\mathrm{log}}_{10}({f}_{\mathrm{rms},\sigma })$ , and ${\mathrm{log}}_{10}({f}_{\mathrm{mean},\sigma })$ . Last, we find marginal evidence for a correlation between line-profile shape, when using the root-mean-square spectrum, ${\mathrm{log}}_{10}{(\mathrm{FWHM}/\sigma )}_{\mathrm{rms}}$ , and the virial coefficient, ${\mathrm{log}}_{10}({f}_{\mathrm{rms},\sigma })$ , and investigate how BLR properties might be related to line-profile shape using caramel models.

The discovery over the last several decades of low- and moderate-luminosity active galactic nuclei (AGNs) in disk-dominated galaxies—which show no “classical” bulges—suggests that secular mechanisms represent an important growth pathway for supermassive black holes in these systems. We present new follow-up NuSTAR observations of the optically elusive AGNs in two bulgeless galaxies, NGC 4178 and J0851+3926. Galaxy NGC 4178 was originally reported as hosting an AGN based on the detection of [Ne v ] mid-infrared emission detected by Spitzer, and based on Chandra X-ray imaging, it has since been argued to host either a heavily obscured AGN or a supernova remnant. Galaxy J0851+3926 was originally identified as an AGN based on its Wide-Field Infrared Survey Explorer mid-IR colors, and follow-up near-infrared spectroscopy previously revealed a hidden broad-line region, offering compelling evidence for an optically elusive AGN. Neither AGN is detected within the new NuSTAR imaging, and we derive upper limits on the hard X-ray 10–24 keV fluxes of 24.2 and 24.1, respectively. The nature of the nuclear activity in NGC 4178 remains inconclusive; it is plausible that the [Ne v ] traces a period of higher activity in the past, but that the AGN is relatively quiescent now. The nondetection in J0851+3926 and multiwavelength properties are consistent with the AGN being heavily obscured.

Theoretical studies predict that the most significant growth of supermassive black holes (SMBHs) occurs in late-stage mergers, coinciding with the manifestation of dual active galactic nuclei (AGNs), and both major and minor mergers are expected to be important for dual AGN growth. In fact, dual AGNs in minor mergers should be signposts for efficient minor-merger-induced SMBH growth for both the more and less massive progenitor. We identified two candidate dual AGNs residing in apparent minor mergers with mass ratios of ∼1:7 and ∼1:30. Sloan Digital Sky Survey (SDSS) fiber spectra show broad and narrow emission lines in the primary nuclei of each merger while only a narrow [O iii ] emission line and a broad and prominent H α /[N ii ] complex is observed in the secondary nuclei. The FWHMs of the broad H α lines in the primary and secondary nuclei are inconsistent in each merger, suggesting that each nucleus in each merger hosts a Type 1 AGN. However, spatially resolved Large Binocular Telescope optical spectroscopy reveals rest-frame stellar absorption features, indicating the secondary sources are foreground stars and that the previously detected broad lines are likely the result of fiber spillover effects induced by the atmospheric seeing at the time of the SDSS observations. This study demonstrates for the first time that optical spectroscopic searches for Type 1/Type 1 pairs similarly suffer from fiber spillover effects as has been observed previously for Seyfert 2 dual AGN candidates. The presence of foreground stars may not have been clear if an instrument with more limited wavelength range or limited sensitivity had been used.

James Webb Space Telescope (JWST) Mid-Infrared Instrument (MIRI) images of the luminous infrared (IR) galaxy VV 114 are presented. This redshift ∼0.020 merger has a western component (VV 114W) rich in optical star clusters and an eastern component (VV 114E) hosting a luminous mid-IR nucleus hidden at UV and optical wavelengths by dust lanes. With MIRI, the VV 114E nucleus resolves primarily into bright NE and SW cores separated by 630 pc. This nucleus comprises 45% of the 15 μ m light of VV 114, with the NE and SW cores having IR luminosities, L _IR (8 − 1000 μ m) ∼ 8 ± 0.8 × 10 ^10 L _⊙ and ∼ 5 ± 0.5 × 10 ^10 L _⊙ , respectively, and IR densities, Σ _IR ≳ 2 ± 0.2 × 10 ^13 L _⊙ kpc ^−2 and ≳ 7 ± 0.7 × 10 ^12 L _⊙ kpc ^−2 , respectively—in the range of Σ _IR for the Orion star-forming core and the nuclei of Arp 220. The NE core, previously speculated to have an active galactic nucleus (AGN), has starburst-like mid-IR colors. In contrast, the VV 114E SW core has AGN-like colors. Approximately 40 star-forming knots with L _IR ∼ 0.02–5 × 10 ^10 L _⊙ are identified, 28% of which have no optical counterpart. Finally, diffuse emission accounts for 40%–60% of the mid-IR emission. Mostly notably, filamentary polycyclic aromatic hydrocarbon (PAH) emission stochastically excited by UV and optical photons accounts for half of the 7.7 μ m light of VV 114. This study illustrates the ability of JWST to detect obscured compact activity and distributed PAH emission in the most extreme starburst galaxies in the local universe.

We have used the Mid-InfraRed Instrument (MIRI) on the James Webb Space Telescope (JWST) to obtain the first spatially resolved, mid-infrared images of IIZw096, a merging luminous infrared galaxy (LIRG) at z = 0.036. Previous observations with the Spitzer Space Telescope suggested that the vast majority of the total IR luminosity ( L _IR ) of the system originated from a small region outside of the two merging nuclei. New observations with JWST/MIRI now allow an accurate measurement of the location and luminosity density of the source that is responsible for the bulk of the IR emission. We estimate that 40%–70% of the IR bolometric luminosity, or 3–5 × 10 ^11 L _⊙ , arises from a source no larger than 175 pc in radius, suggesting a luminosity density of at least 3–5 × 10 ^12 L _⊙ kpc ^−2 . In addition, we detect 11 other star-forming sources, five of which were previously unknown. The MIRI F1500W/F560W colors of most of these sources, including the source responsible for the bulk of the far-IR emission, are much redder than the nuclei of local LIRGs. These observations reveal the power of JWST to disentangle the complex regions at the hearts of merging, dusty galaxies.

The nearby, luminous infrared galaxy NGC 7469 hosts a Seyfert nucleus with a circumnuclear star-forming ring and is thus the ideal local laboratory for investigating the starburst–AGN (active galactic nucleus) connection in detail. We present integral-field observations of the central 1.3 kpc region in NGC 7469 obtained with the JWST Mid-InfraRed Instrument. Molecular and ionized gas distributions and kinematics at a resolution of ∼100 pc over the 4.9–7.6 μ m region are examined to study the gas dynamics influenced by the central AGN. The low-ionization [Fe ii ] λ 5.34 μ m and [Ar ii ] λ 6.99 μ m lines are bright on the nucleus and in the starburst ring, as opposed to H _2 S(5) λ 6.91 μ m, which is strongly peaked at the center and surrounding ISM. The high-ionization [Mg v ] line is resolved and shows a broad, blueshifted component associated with the outflow. It has a nearly face-on geometry that is strongly peaked on the nucleus, where it reaches a maximum velocity of −650 km s ^−1 , and extends about 400 pc to the east. Regions of enhanced velocity dispersion in H _2 and [Fe ii ] ∼ 180 pc from the AGN that also show high L (H _2 )/ L (PAH) and L ([Fe ii ])/ L (Pf α ) ratios to the W and N of the nucleus pinpoint regions where the ionized outflow is depositing energy, via shocks, into the dense interstellar medium between the nucleus and the starburst ring. These resolved mid-infrared observations of the nuclear gas dynamics demonstrate the power of JWST and its high-sensitivity integral-field spectroscopic capability to resolve feedback processes around supermassive black holes in the dusty cores of nearby luminous infrared galaxies.

We present James Webb Space Telescope (JWST) Mid-Infrared Instrument (MIRI) integral-field spectroscopy of the nearby merging, luminous infrared galaxy, NGC 7469. This galaxy hosts a Seyfert type-1.5 nucleus, a highly ionized outflow, and a bright, circumnuclear star-forming ring, making it an ideal target to study active galactic nucleus (AGN) feedback in the local universe. We take advantage of the high spatial/spectral resolution of JWST/MIRI to isolate the star-forming regions surrounding the central active nucleus and study the properties of the dust and warm molecular gas on ∼100 pc scales. The starburst ring exhibits prominent polycyclic aromatic hydrocarbon (PAH) emission, with grain sizes and ionization states varying by only ∼30%, and a total star formation rate of 10–30 M _⊙ yr ^−1 derived from fine structure and recombination emission lines. Using pure rotational lines of H _2 we detect 1.2 × 10 ^7 M _⊙ of warm molecular gas at a temperature higher than 200 K in the ring. All PAH bands get significantly weaker toward the central source, where larger and possibly more ionized grains dominate the emission, likely the result of the ionizing radiation and/or the fast wind emerging from the AGN. The small grains and warm molecular gas in the bright regions of the ring however display properties consistent with normal star-forming regions. These observations highlight the power of JWST to probe the inner regions of dusty, rapidly evolving galaxies for signatures of feedback and inform models that seek to explain the coevolution of supermassive black holes and their hosts.

Abstract Background Nowadays, 3D planning and static for dynamic aids play an increasing role in oral rehabilitation of the masticatory apparatus with dental implants. The aim of this study is to compare the accuracy of implant placement using a 3D-printed drilling guide and an intraoral real-time dynamic navigation system. Methods A total of 60 implants were placed on 12 partially edentulous lower jaw models. 30 were placed with pilot drilling guides, the other half with dynamic navigation (DENACAM®). In addition, implant placement in interdental gaps and free-end situations were investigated. Accuracy was assessed by cone-beam computed tomography (CBCT). Results Both systems achieved clinically acceptable results, yet more accurate results regarding the offset of implant base and tip in several spatial dimensions were achieved using drilling guides (each p

Virtual reality (VR) is increasingly used in learning and can be experienced with a head-mounted display as a 3D immersive version (immersive virtual reality [IVR]) or with a PC (or another computer) as a 2D desktop-based version (desktop virtual reality [DVR]). A research gap is the effect of IVR and DVR on learners’ skill retention. To address this gap, we designed an experiment in which learners were trained and tested for the assembly of a procedural industrial task. We found nonsignificant differences in the number of errors, the time to completion, satisfaction, self-efficacy, and motivation. The results support the view that DVR and IVR are similarly useful for learning retention. These insights may help researchers and practitioners to decide which form of VR they should use.

Mast cells are the major effector cells in immunoglobulin E (IgE)-mediated allergy. The high affinity IgE receptor FcεRI, as well as G protein-coupled receptors (GPCRs) on the mast cell surface signals to phosphoinositide 3-kinase γ (PI3Kγ) to initiate degranulation, cytokine release, and chemotaxis. PI3Kγ is therefore considered as a target for treatment of allergic disorders. However, leukocyte PI3Kγ is key to many functions in innate and adaptive immunity, and attenuation of host defense mechanisms is an expected adverse effect that complicates treatment of chronic illnesses. PI3Kγ operates as a p110γ/p84 or p110γ/p101 complex, where p110γ/p84 requires Ras activation. Here we investigated if modulation of Ras-isoprenylation could target PI3Kγ activity to attenuate PI3Kγ-dependent mast cell responses without impairment of macrophage functions. In murine bone marrow-derived mast cells, GPCR stimulation triggers activation of N-Ras and H-Ras isoforms, which is followed by the phosphorylation of protein kinase B (PKB/Akt) relayed through PI3Kγ. Although K-Ras is normally not activated in Ras wild-type cells, it is able to compensate for genetically deleted N- and H-Ras isoforms. Inhibition of Ras isoprenylation with farnesyltransferase inhibitor FTI-277 leads to a significant reduction of mast cell degranulation, cytokine production, and migration. Complementation experiments expressing PI3Kγ adaptor proteins p84 or p101 demonstrated a differential sensitivity towards Ras-inhibition depending on PI3Kγ complex composition. Mast cell responses are exclusively p84-dependent and were effectively controlled by FTI-277. Similar results were obtained when GTP-Ras was inactivated by overexpression of the GAP-domain of Neurofibromin-1 (NF-1). Unlike mast cells, macrophages express p84 and p101 but are p101-dominated and thus remain functional under treatment with FTI-277. Our work demonstrates that p101 and p84 have distinct physiological roles, and that Ras dependence of PI3Kγ signaling differs between cell types. FTI-277 reduces GPCR-activated PI3Kγ responses in p84-expressing but not p101-containing bone marrow derived cells. However, prenylation inhibitors have pleiotropic effects beyond Ras and non-tolerable side-effects that disfavor further clinical validation. Statins are, however, clinically well-established drugs that have previously been proposed to block mast cell degranulation by interference with protein prenylation. We show here that Simvastatin inhibits mast cell degranulation, but that this does not occur via Ras-PI3Kγ pathway alterations.

The assessment of an instrument’s conceptual framework as prerequisite for conducting further analyses has been advocated for decades. Multidimensional instruments posit several components that are each expected to be homogeneous but distinct from each other. However, validity evidence supporting the proposed internal structure is often missing. This leaves researchers and practitioners who are interested in a certain instrument in a precarious situation: Before starting their own data collection, they do not know whether dimensions adequately discriminate from each other and thus whether they can have confidence in any interpretation of these dimensions. Adapting the Fornell–Larcker criterion, we propose estimating distinctiveness between dimensions by using nothing but the most commonly reported statistics: Cronbach’s alpha and the correlation matrix between the manifest composite scores of the dimensions in question. A simulation study demonstrates the usefulness of this “manifest Fornell–Larcker criterion” in providing an easily assessable method for vetting existing instruments, whereas a systematic literature review shows the necessity to do so even for instruments published in well-received journals.

Buparlisib/BKM120 is in phase 3 clinical trials as a phosphoinositide 3-kinase (PI3K) inhibitor. Here, Bohnackeret al. combine chemical biology and structural biology approaches to segregate BKM120’s biological actions, and suggest that it causes mitotic arrest predominantly by binding microtubules and disrupting their dynamics.

Agriculture plays a vital role in the South African economy, as well as in the production of maize for food. Genetically modified maize is transformed to encode for crystalline (Cry) proteins found in Bacillus thuringiensis (Bt) and is referred to as Bt maize. Ingestion of specific Cry proteins causes the death of target insects that cause harm to maize plants. Bt crops, along with herbicides such as glyphosate and 2,4-dichloro- phenoxyacetic acid (2,4-D), are widely adopted as part of the South African farming regime that aims to increase crop yield and reduce costs of production. As chemical compounds used in agriculture often end up in water sources, their presence should be monitored. There are many such monitoring programmes worldwide, but not in South Africa. We screened surface water sources in a maize-dominated agricultural area in the North West Province in South Africa for the presence of Cry1Ab, glyphosate and 2,4-D using enzyme-linked immunosorbent assays (ELISAs). Cry1Ab was not detected at any site; glyphosate was below the limit of detection at most of the sites but one sample had quantifiable traces of glyphosate; and 2,4-D was detected at all the sites. The concentrations of 2,4-D exceeded those for drinking water according to European guidelines, thus highlighting the need for regular monitoring of these compounds. Many people depend on untreated water resources, which may be contaminated by toxic agricultural chemicals. This report is the first on levels of these target compounds in South African water systems. Significance: • This report is the first on the presence of glyphosate, 2,4-D and Cry1Ab in the South African aquatic environment. • Concentrations of 2,4-D in South African surface waters exceed the European guideline for drinking water, indicating a risk to people using these water sources. • These preliminary results highlight the need to regularly monitor for the presence of glyphosate, 2,4-D and Cry1Ab in water resources in South Africa.

Hyperparameters and learning algorithms for neuromorphic hardware are usually chosen by hand to suit a particular task. In contrast, networks of neurons in the brain were optimized through extensive evolutionary and developmental processes to work well on a range of computing and learning tasks. Occasionally this process has been emulated through genetic algorithms, but these require themselves hand-design of their details and tend to provide a limited range of improvements. We employ instead other powerful gradient-free optimization tools, such as cross-entropy methods and evolutionary strategies, in order to port the function of biological optimization processes to neuromorphic hardware. As an example, we show these optimization algorithms enable neuromorphic agents to learn very efficiently from rewards. In particular, meta-plasticity, i.e., the optimization of the learning rule which they use, substantially enhances reward-based learning capability of the hardware. In addition, we demonstrate for the first time Learning-to-Learn benefits from such hardware, in particular, the capability to extract abstract knowledge from prior learning experiences that speeds up the learning of new but related tasks. Learning-to-Learn is especially suited for accelerated neuromorphic hardware, since it makes it feasible to carry out the required very large number of network computations.

Agriculture is fundamental for human survival through food production and is performed in ecosystems that, while simplified, still operate along ecological principles and retain complexity. Agricultural plants are thus part of ecological systems, and interact in complex ways with the surrounding terrestrial, soil, and aquatic habitats. We discuss three case studies that demonstrate how agricultural solutions to pest and weed control, if they overlook important ecological and evolutionary factors, cause “surprises”: (i) the fast emergence of resistance against the crop-inserted Bt-toxin in South Africa, (ii) the ecological changes generated by Bt-cotton landscapes in China, and (iii) the decline of the monarch butterfly, Danaus plexippus, in North America. The recognition that we work with complex systems is in itself important, as it should limit the belief in reductionist solutions. Agricultural practices lacking eco-evolutionary understanding result in “surprises” like resistance evolution both in weeds and pest insects, risking the reappearance of the “pesticide treadmill”—with increased use of toxic pesticides as the follow-up. We recommend prioritization of research that counteracts the tendencies of reductionist approaches. These may be beneficial on a short term, but with trade-off costs on a medium- to long-term. Such costs include loss of biodiversity, ecosystem services, long-term soil productivity, pollution, and reduced food quality.

The insecticidal crystal proteins from Bacillus thuringiensis (Bt) are widely-used biopesticides that are used both as Bt spore-crystal preparations in sprayable formulations and as activated toxins in genetically modified (GM) plants. Models for their modes of action have been proposed but many issues remain unresolved. Among those is the role of commensal gut bacteria in target insect death: previous studies showed that antibiotics attenuate the toxicity of Bt sprays. We tested whether antibiotics interfere with the effects of GM plant-produced Bt toxins in larvae of two Lepidopteran species, the European corn borer Ostrinia nubilalis and the cotton leafworm Spodoptera littoralis. The larvae were reared on artificial diet with or without antibiotics and, thereafter, fed two varieties of Bt GM maize in comparison to conventional non-Bt maize leaves sprayed with antibiotic solution and/or with a Bt formulation. Antibiotics significantly reduced or delayed the toxicity of Cry toxins, although to a lesser extent than previously reported for Bt-sprays. This supports the hypothesis that Cry toxins induce mortality by themselves in the absence of Bt bacteria and spores, and of commensal gut bacteria. However, larvae that were not treated with antibiotics died faster and at a higher rate which was further compounded by plant variety and species sensitivity. These findings support a hypothesis that toxicemia alone can inflict significant mortality. However, in the absence of antibiotics, the gut bacteria likely enhance the Cry toxin effect by inflicting, additionally, bacterial septicemia. This has important implications in field situations where antibiotic substances are present—e.g., from manure of animals from conventional production systems—and for ecotoxicological testing schemes of Bt toxins and nontarget organisms that are often using artificial diets enriched with high concentrations of antibiotics.

Accumulation of cholesterol by macrophage uptake of LDL is a key event in the formation of atherosclerotic plaques. Previous research has shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) is present in atherosclerotic plaques and promotes aortic lipid accumulation. However, it has not been determined whether murine GM-CSF-differentiated macrophages take up LDL to become foam cells. GM-CSF-differentiated macrophages from LDL receptor-null mice were incubated with LDL, resulting in massive macrophage cholesterol accumulation. Incubation of LDL receptor-null or wild-type macrophages with increasing concentrations of 125I-LDL showed nonsaturable macrophage LDL uptake that was linearly related to the amount of LDL added, indicating that LDL uptake was mediated by fluid-phase pinocytosis. Previous studies suggest that phosphoinositide 3-kinases (PI3K) mediate macrophage fluid-phase pinocytosis, although the isoform mediating this process has not been determined. Because PI3Kγ is known to promote aortic lipid accumulation, we investigated its role in mediating macrophage fluid-phase pinocytosis of LDL. Wild-type macrophages incubated with LDL and the PI3Kγ inhibitor AS605240 or PI3Kγ-null macrophages incubated with LDL showed an ∼50% reduction in LDL uptake and cholesterol accumulation compared with wild-type macrophages incubated with LDL only. These results show that GM-CSF-differentiated murine macrophages become foam cells by fluid-phase pinocytosis of LDL and identify PI3Kγ as contributing to this process.

Modified vaccinia virus Ankara (MVA) is the vector of choice for human and veterinary applications due to its strong safety profile and immunogenicity in vivo. The use of MVA and MVA-vectored vaccines against human and animal diseases must comply with regulatory requirements as they pertain to environmental risk assessment, particularly the characterization of potential adverse effects to humans, animals and the environment. MVA and recombinant MVA are widely believed to pose low or negligible risk to ecosystem health. However, key aspects of MVA biology require further research in order to provide data needed to evaluate the potential risks that may occur due to the use of MVA and MVA-vectored vaccines. The purpose of this paper is to identify knowledge gaps in the biology of MVA and recombinant MVA that are of relevance to its hazard characterization and discuss ongoing and future experiments aimed at providing data necessary to fill in the knowledge gaps. In addition, we presented arguments for the inclusion of uncertainty analysis and experimental investigation of verifiable worst-case scenarios in the environmental risk assessment of MVA and recombinant MVA. These will contribute to improved risk assessment of MVA and recombinant MVA vaccines.

Small-scale subsistence farmers in South Africa have been introduced to genetically modified (GM) crops for more than a decade. Little is known about i) the extent of transgene introgression into locally recycled seed, ii) what short and long-term ecological and socioeconomic impacts such mixing of seeds might have, iii) how the farmers perceive GM crops, and iv) to what degree approval conditions are followed and controlled. This study conducted in the Eastern Cape, South Africa, aims primarily at addressing the first of these issues. We analysed for transgenes in 796 individual maize plants (leaves) and 20 seed batches collected in a village where GM insect resistant maize was previously promoted and grown as part of an governmental agricultural development program over a seven year period (2001-2008). Additionally, we surveyed the varieties of maize grown and the farmers' practices of recycling and sharing of seed in the same community (26 farmers were interviewed). Recycling and sharing of seeds were common in the community and may contribute to spread and persistence of transgenes in maize on a local or regional level. By analysing DNA we found that the commonly used transgene promoter p35s occurred in one of the 796 leaf samples (0.0013%) and in five of the 20 seed samples (25%). Three of the 20 seed samples (15%) included herbicide tolerant maize (NK603) intentionally grown by the farmers from seed bought from local seed retailers or acquired through a currently running agricultural development program. The two remaining positive seed samples (10%) included genes for insect resistance (from MON810). In both cases the farmers were unaware of the transgenes present. In conclusion, we demonstrate that transgenes are mixed into seed storages of small-scale farming communities where recycling and sharing of seeds are common, i.e. spread beyond the control of the formal seed system.

All class I phosphoinositide 3-kinases (PI3Ks) associate tightly with regulatory subunits through interactions that have been thought to be constitutive. PI3Kγ is key to the regulation of immune cell responses activated by G protein-coupled receptors (GPCRs). Remarkably we find that PKCβ phosphorylates Ser582 in the helical domain of the PI3Kγ catalytic subunit p110γ in response to clustering of the high-affinity IgE receptor (FcεRI) and/or store-operated Ca²⁺- influx in mast cells. Phosphorylation of p110γ correlates with the release of the p84 PI3Kγ adapter subunit from the p84-p110γ complex. Ser582 phospho-mimicking mutants show increased p110γ activity and a reduced binding to the p84 adapter subunit. As functional p84-p110γ is key to GPCR-mediated p110γ signaling, this suggests that PKCβ-mediated p110γ phosphorylation disconnects PI3Kγ from its canonical inputs from trimeric G proteins, and enables p110γ to operate downstream of Ca²⁺ and PKCβ. Hydrogen deuterium exchange mass spectrometry shows that the p84 adaptor subunit interacts with the p110γ helical domain, and reveals an unexpected mechanism of PI3Kγ regulation. Our data show that the interaction of p110γ with its adapter subunit is vulnerable to phosphorylation, and outline a novel level of PI3K control.

During atherosclerosis, low-density lipoprotein (LDL)-derived cholesterol accumulates in macrophages to form foam cells. Macrophage uptake of LDL promotes foam cell formation but the mechanism mediating this process is not clear. The present study investigates the mechanism of LDL uptake for macrophage colony-stimulating factor (M-CSF)-differentiated murine bone marrow-derived macrophages. LDL receptor-null (LDLR-/-) macrophages incubated with LDL showed non-saturable accumulation of cholesterol that did not down-regulate for the 24 h examined. Incubation of LDLR-/- macrophages with increasing concentrations of (125)I-LDL showed non-saturable macrophage LDL uptake. A 20-fold excess of unlabeled LDL had no effect on (125)I-LDL uptake by wild-type macrophages and genetic deletion of the macrophage scavenger receptors CD36 and SRA did not affect (125)I-LDL uptake, showing that LDL uptake occurred by fluid-phase pinocytosis independently of receptors. Cholesterol accumulation was inhibited approximately 50% in wild-type and LDLR-/- mice treated with LY294002 or wortmannin, inhibitors of all classes of phosphoinositide 3-kinases (PI3K). Time-lapse, phase-contrast microscopy showed that macropinocytosis, an important fluid-phase uptake pathway in macrophages, was blocked almost completely by PI3K inhibition with wortmannin. Pharmacological inhibition of the class I PI3K isoforms alpha, beta, gamma or delta did not affect macrophage LDL-derived cholesterol accumulation or macropinocytosis. Furthermore, macrophages from mice expressing kinase-dead class I PI3K beta, gamma or delta isoforms showed no decrease in cholesterol accumulation or macropinocytosis when compared with wild-type macrophages. Thus, non-class I PI3K isoforms mediated macropinocytosis in these macrophages. Further characterization of the components necessary for LDL uptake, cholesterol accumulation, and macropinocytosis identified dynamin, microtubules, actin, and vacuolar type H(+)-ATPase as contributing to uptake. However, Pak1, Rac1, and Src-family kinases, which mediate fluid-phase pinocytosis in certain other cell types, were unnecessary. In conclusion, our findings provide evidence that targeting those components mediating macrophage macropinocytosis with inhibitors may be an effective strategy to limit macrophage accumulation of LDL-derived cholesterol in arteries.