We present new subarcsecond-resolution Karl G. Jansky Very Large Array (VLA) imaging at 10 GHz of 155 ultraluminous (Lbol ∼ 1011.7-1014.2 L ) and heavily obscured quasars with redshifts z ∼ 0.4-3. ...The sample was selected to have extremely red mid-infrared-optical color ratios based on data from the Wide-Field Infrared Survey Explorer (WISE) along with a detection of bright, unresolved radio emission from the NRAO VLA Sky Survey (NVSS) or Faint Images of the Radio Sky at Twenty cm Survey. Our high-resolution VLA observations have revealed that the majority of the sources in our sample (93 out of 155) are compact on angular scales <0 2 (≤1.7 kpc at z ∼ 2). The radio luminosities, linear extents, and lobe pressures of our sources are similar to young radio active galactic nuclei (e.g., gigahertz-peaked spectrum GPS and compact steep-spectrum CSS sources), but their space density is considerably lower. Application of a simple adiabatic lobe expansion model suggests relatively young dynamical ages (∼104-7 yr), relatively high ambient ISM densities (∼1-104 cm−3), and modest lobe expansion speeds (∼30-10,000 km s−1). Thus, we find our sources to be consistent with a population of newly triggered, young jets caught in a unique evolutionary stage in which they still reside within the dense gas reservoirs of their hosts. Based on their radio luminosity function and dynamical ages, we estimate that only ∼20% of classical large-scale FR I/II radio galaxies could have evolved directly from these objects. We speculate that the WISE-NVSS sources might first become GPS or CSS sources, of which some might ultimately evolve into larger radio galaxies.
Context. Remnant radio galaxies represent the final dying phase of radio galaxy evolution in which the jets are no longer active. Remnants are rare in flux-limited samples, comprising at most a few ...percent. As a result of their rarity and because they are difficult to identify, this dying phase remains poorly understood and the luminosity evolution is largely unconstrained. Aims. Here we present the discovery and detailed analysis of a large (700 kpc) remnant radio galaxy with a low surface brightness that has been identified in LOFAR images at 150 MHz. Methods. By combining LOFAR data with new follow-up Westerbork observations and archival data at higher frequencies, we investigated the source morphology and spectral properties from 116 to 4850 MHz. By modelling the radio spectrum, we probed characteristic timescales of the radio activity. Results. The source has a relatively smooth, diffuse, amorphous appearance together with a very weak central compact core that is associated with the host galaxy located at z = 0.051. From our ageing and morphological analysis it is clear that the nuclear engine is currently switched off or, at most, active at a very low power state. We find that the source has remained visible in the remnant phase for about 60 Myr, significantly longer than its active phase of 15 Myr, despite being located outside a cluster. The host galaxy is currently interacting with another galaxy located at a projected separation of 15 kpc and a radial velocity offset of ~ 300 km s-1. This interaction may have played a role in the triggering and/or shut-down of the radio jets. Conclusions. The spectral shape of this remnant radio galaxy differs from most of the previously identified remnant sources, which show steep or curved spectra at low to intermediate frequencies. Our results demonstrate that remnant radio galaxies can show a wide range of evolutionary paths and spectral properties. In light of this finding and in preparation for new-generation deep low-frequency surveys, we discuss the selection criteria to be used to select representative samples of these sources.
Within the MAPK/RAS pathway, there exists a plethora of protein-protein interactions (PPIs). For many years, scientists have focused efforts on drugging KRAS and its effectors in hopes to provide ...much needed therapies for patients with
-mutant driven cancers. In this review, we focus on recent strategies to inhibit RAS-signaling via disrupting PPIs associated with SOS1, RAF, PDEδ, Grb2, and RAS.
The mechanism by which lithium (Li+) inhibits the protein kinase glycogen synthase kinase-3 (GSK-3) is unknown. Here, we demonstrate that Li+ is a competitive inhibitor of GSK-3 with respect to ...magnesium (Mg2+), but not to substrate or ATP. This mode of inhibition is conserved between mammalian and Dictyostelium GSK-3 isoforms, and is not experienced with other group I metal ions. As a consequence, the potency of Li+ inhibition is dependent on Mg2+ concentration. We also found that GSK-3 is sensitive to chelation of free Mg2+ by ATP and is progressively inhibited when ATP concentrations exceed that of Mg2+. Given the cellular concentrations of ATP and Mg2+, our results indicate that Li+ will have a greater effect on GSK-3 activity in vivo than expected from in vitro studies and this may be a factor relevant to its use in the treatment of depression.
The Illicium sesquiterpenes are a family of natural products containing over 100 highly oxidized and structurally complex members, many of which display interesting biological activities. This ...comprehensive account chronicles the evolution of a semisynthetic strategy toward these molecules from (+)-cedrol, seeking to emulate key aspects of their presumed biosynthesis. An initial route generated lower oxidation state analogs but failed in delivering a crucial hydroxy group in the final step. Insight gathered during these studies, however, ultimately led to a synthesis of the pseudoanisatinoids along with the allo-cedrane natural product 11-O-debenzoyltashironin. A second-generation strategy was then developed to access the more highly oxidized majucinoid compounds including jiadifenolide and majucin itself. Overall, one dozen natural products can be accessed from an abundant and inexpensive terpene feedstock. A multitude of general observations regarding site-selective C(sp3)–H bond functionalization reactions in complex polycyclic architectures are reported.
Background Tuberous sclerosis complex (TSC) is a rare genetic multisystemic disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes. It is characterised by hyperactivation of ...the mechanistic target of rapamycin complex 1 (mTORC1) pathway and has severe neurodevelopmental and neurological components including autism, intellectual disability and epilepsy. In human and rodent models, loss of the TSC proteins causes neuronal hyperexcitability and synaptic dysfunction, although the consequences of these changes for the developing central nervous system are currently unclear. Methods Here we apply multi-electrode array-based assays to study the effects of TSC2 loss on neuronal network activity using autism spectrum disorder (ASD) patient-derived iPSCs. We examine both temporal synchronisation of neuronal bursting and spatial connectivity between electrodes across the network. Results We find that ASD patient-derived neurons with a functional loss of TSC2, in addition to possessing neuronal hyperactivity, develop a dysfunctional neuronal network with reduced synchronisation of neuronal bursting and lower spatial connectivity. These deficits of network function are associated with elevated expression of genes for inhibitory GABA signalling and glutamate signalling, indicating a potential abnormality of synaptic inhibitory-excitatory signalling. mTORC1 activity functions within a homeostatic triad of protein kinases, mTOR, AMP-dependent protein Kinase 1 (AMPK) and Unc-51 like Autophagy Activating Kinase 1 (ULK1) that orchestrate the interplay of anabolic cell growth and catabolic autophagy while balancing energy and nutrient homeostasis. The mTOR inhibitor rapamycin suppresses neuronal hyperactivity, but does not increase synchronised network activity, whereas activation of AMPK restores some aspects of network activity. In contrast, the ULK1 activator, LYN-1604, increases the network behaviour, shortens the network burst lengths and reduces the number of uncorrelated spikes. Limitations Although a robust and consistent phenotype is observed across multiple independent iPSC cultures, the results are based on one patient. There may be more subtle differences between patients with different TSC2 mutations or differences of polygenic background within their genomes. This may affect the severity of the network deficit or the pharmacological response between TSC2 patients. Conclusions Our observations suggest that there is a reduction in the network connectivity of the in vitro neuronal network associated with ASD patients with TSC2 mutation, which may arise via an excitatory/inhibitory imbalance due to increased GABA-signalling at inhibitory synapses. This abnormality can be effectively suppressed via activation of ULK1.
Aims
Levels and sources of faecal indicator bacteria (FIB) in an ephemeral Florida river were assessed under different rainfall/flow patterns to explore the effects of rainfall on water quality.
...Methods and Results
Quantitative PCR for sewage markers human‐associated Bacteroides HF183 and human polyomaviruses (HPyVs) and PCR for ruminant faecal markers were used to explore contamination sources. Escherichia coli, faecal coliform and enterococci levels consistently exceeded recreational water quality criteria, and sediment FIB levels were about 100‐fold higher compared with water. HPyVs detections cooccurred with HF183, which was frequently detected near septic systems. Ruminant markers were detected only in livestock‐grazing areas. Significantly greater faecal coliform and E. coli concentrations were observed under no‐flow conditions and the levels of faecal coliforms in water column and sediments were negatively correlated with duration since last rain event.
Conclusions
Septic systems and cattle grazing in this watershed contributed to the formation of FIB reservoirs in sediments, which were persistent following prolonged rainfall.
Significance and Impact of the Study
Ephemeral water bodies that flow only under the direct influence of recent rainfall are rarely studied. FIB levels in the New River in Florida were greater during dry weather than wet weather, which contrasts with most observations and may be attributed to bacterial reservoirs formed in still pool, sediments and water‐saturated soils in this subtropical environment.
Shotgun metagenomic sequencing of the collective genomic information carried across microbial communities is emerging as a powerful approach for monitoring antibiotic resistance in environmental ...matrices. Metagenomics is advantageous in that known and putative antibiotic resistance genes (ARGs) (i.e., the resistome) can be screened simultaneously without a priori selection of targets. Additionally, as new ARGs are discovered and catalogued, stored sequencing data can be reanalyzed to assess the prevalence of emerging genes or pathogens. However, best practices for metagenomic data generation and processing are needed to support comparability across space and time. To support reproducible downstream analysis, guidance is first needed with respect to sampling design, sample preservation and storage, DNA extraction, library preparation, sequencing depth, and experimental controls. Here we conducted a systematic review to assess current practices for the application of metagenomics for AR profiling of wastewater, recycled water, and surface water and to offer recommendations to support comparability in the collection, production, and analysis of resulting data. Based on integrated analysis of findings and data reported across 95 articles identified, a field to benchtop metagenomic workflow is discussed for optimizing the representativeness and comparability of generated data. Through the reanalysis of 1474 publicly-available metagenomes, appropriate sequencing depths per environment and uniform normalization strategies are provided. Further, there is opportunity to harness the quantitative capacity of metagenomics more overtly through inclusion of sequencing controls. The recommendations will amplify the overall value of the metagenomic data generated to support within and between study comparisons, now and in the future.
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