List Of Targets Research Articles

Exoplanets across galactic stellar populations with PLATO. Estimating exoplanet yields around FGK stars for the thin disk, thick disk, and stellar halo

The vast majority of exoplanet discoveries to date have occurred around stars in the solar neighbourhood, with chemical compositions comparable to that of the Sun. However, models suggest that planetary systems in different Galactic environments, with varying dynamical histories and chemical abundances, may exhibit distinct characteristics, which can help improve our understanding of planet formation processes. This study aims to assess the potential of the upcoming PLATO mission to investigate exoplanet populations around stars in diverse Galactic environments, specifically focusing on the Milky Way thin disk, thick disk, and stellar halo. We aim to quantify PLATO's ability to detect planets in each environment and determine how these observations could constrain planet formation models. Beginning with the all-sky PLATO Input Catalogue, we kinematically classified the 2.4 million FGK stars into their respective Galactic components. For the sub-sample of stars in the long-observation LOPS2 and LOPN1 PLATO fields, we estimated planet occurrence rates using the New Generation Planet Population Synthesis (NGPPS) dataset. Combining these estimates with a PLATO detection efficiency model, we predicted the expected planet yields for each Galactic environment during a nominal 2+2 year mission. Based on our analysis, PLATO is likely to detect at least 400 exoplanets around the alpha -enriched thick disk stars. The majority of those planets are expected to be super-Earths and sub-Neptunes with radii between 2 and 10 $R_ and orbital periods between 2 and 50 days, which is ideal for studying the link between the radius valley and stellar chemistry. For the metal-poor halo, PLATO is likely to detect between 1 and 80 planets with periods between 10 and 50 days, depending on the potential existence of a metallicity threshold for planet formation. The PLATO fields contain more than 3,400 potential target stars with Fe/H < -0.6, which will help improve our understanding of planets around metal-poor stars. We identified a specific target list of 47 (kinematically classified) halo stars in the high-priority, high-signal-to-noise PLATO P1 sample, offering prime opportunities in the search for planets in metal-poor environments. PLATO's unique capabilities and large field of view position it as a valuable tool for studying planet formation across the diverse Galactic environments of the Milky Way. By probing exoplanet populations around stars with a varying chemical composition, PLATO will provide helpful insights into the connection between stellar chemistry and planet formation.

STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1.

Cohesin complexes carrying STAG1 or STAG2 organize the genome into chromatin loops. STAG2 loss-of-function mutations promote metastasis in Ewing sarcoma, a pediatric cancer driven by the fusion transcription factor EWS::FLI1. We integrated transcriptomic data from patients and cellular models to identify a STAG2-dependent gene signature associated with worse prognosis. Subsequent genomic profiling and high-resolution chromatin interaction data from Capture Hi-C indicated that cohesin-STAG2 facilitates communication between EWS::FLI1-bound long GGAA repeats, presumably acting as neoenhancers, and their target promoters. Changes in CTCF-dependent chromatin contacts involving signature genes, unrelated to EWS::FLI1 binding, were also identified. STAG1 is unable to compensate for STAG2 loss and chromatin-bound cohesin is severely decreased, while levels of the processivity factor NIPBL remain unchanged, likely affecting DNA looping dynamics. These results illuminate how STAG2 loss modifies the chromatin interactome of Ewing sarcoma cells and provide a list of potential biomarkers and therapeutic targets.

Multi-modal scene graph inspired policy for visual navigation

Visual navigation needs the agent locate the given target with visual perception. To enable robots to effectively execute tasks, combining large language models (LLMs) with multi-modal inputs in navigation is necessary. While LLMs offer rich semantic knowledge, they lack specific real-world information and real-time interaction capabilities. This paper introduces a Multi-modal Scene Graph (MMSG) navigation framework that aligns LLMs with visual perception models to predict next steps. Firstly, a multi-modal scene dataset is constructed, containing triplets of object-relations-target words. We provide target words and lists of existing objects in the scene to generate a large number of instructions and corresponding action plans for GPT-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$-$$\\end{document}3.5. The generated data is then utilized for pre-train LLM for path planning. During inference, we discover objects in the scene by extending the DETR visual object detector to multi-view RGB image collected from different reachable positions. Experimental results show that path planning generated from MMSG outperforms state-of-the-art methods, indicating its feasibility in complex environments. We evaluate our methods on the ProTHOR dataset and show superior navigation performance.

Database of Candidate Targets for the LIFE Mission

We present the database of potential targets for the Large Interferometer For Exoplanets (LIFE), a space-based mid-infrared nulling interferometer mission proposed for the Voyage 2050 science program of the European Space Agency. The database features stars, their planets and disks, main astrophysical parameters, and ancillary observations. It allows users to create target lists based on various criteria to predict, for instance, exoplanet detection yields for the LIFE mission. As such, it enables mission design trade-offs, provides context for the analysis of data obtained by LIFE, and flags critical missing data. Work on the database is in progress, but given its relevance to LIFE and other space missions, including the Habitable Worlds Observatory, we present its main features here. A preliminary version of the LIFE database is publicly available on the German Astrophysical Virtual Observatory.

Dynamical Viability Assessment for Habitable Worlds Observatory Targets

Exoplanetary science is increasingly prioritizing efforts toward direct imaging of planetary systems, with emphasis on those that may enable the detection and characterization of potentially habitable exoplanets. The recent 2020 Astronomy and Astrophysics decadal survey recommended the development of a space-based direct imaging mission that has subsequently been referred to as the Habitable Worlds Observatory (HWO). A fundamental challenge in the preparatory work for the HWO search for exo-Earths is the selection of suitable stellar targets. Much of the prior efforts regarding the HWO targets has occurred within the context of exoplanet surveys that have characterized the stellar properties for the nearest stars. The preliminary input catalog for HWO consists of 164 stars, of which 30 are known exoplanet hosts to 70 planets. Here, we provide a dynamical analysis for these 30 systems, injecting a terrestrial planet mass into the habitable zone (HZ) and determining the constraints on stable orbit locations due to the influence of the known planets. For each system, we calculate the percentage of the HZ that is dynamically viable for the potential presence of a terrestrial planet, providing an additional metric for inclusion of the stars within the HWO target list. Our analysis shows that, for 11 of the systems, less than 50% of the HZ is dynamically viable, primarily due to the presence of giant planets whose orbits pass near or through the HZ. These results demonstrate the impact that known system architectures can have on direct imaging target selection and overall system habitability.

Large scale screening and quantification of micropollutants in fish from the coastal waters of Cochin, India: Analytical method development and health risk assessment

Urban estuarine and coastal water receive several micropollutants through industrial and agricultural influxes. The bioaccumulation of these micropollutants in fish and their entry into the coastal population's food chain raises significant food safety concerns. Hence, a comprehensive analytical method was developed for ultra-trace level quantification of 345 micropollutants in fish. The optimized sample preparation method could extract compounds suitable for both GC–MS/MS and LC-MS/MS analysis simultaneously. The target list of contaminants included 278 agricultural pesticides and also 102 endocrine disruptors covering polyaromatic hydrocarbons, polychlorinated biphenyls, organochlorines, and endocrine-disrupting pesticides. The GC–MS/MS with large volume injection (LVI) technique, and LC-MS/MS operating in MRM mode, achieved an LOQ of <2.00 ng/g for most of the analytes. The extraction strategy involved tri-phase partitioning between water, acidified acetonitrile, and hexane, followed by salting out. Dispersive solid phase cleanup (dSPE) with C18, Z-Sep+, CaCl2, and MgSO4 was able to reduce the matrix influence, and the method achieved satisfactory recovery in the range of 70.0–120.0 % for all the target analytes. The repeatability and reproducibility relative standard deviation values of the measured analytes were <20.0 %, and the Horwitz ratio values were well below 2. The method was used to accurately measure the target micropollutants in fish from the Cochin estuary, the highly urbanized portion of the Vembanad Lake, and an important Ramsar site. At least one or more of the 41 different micropollutants were identified and quantified in about 90.7 % of the 108 samples analyzed. The importance of large-scale screening and trace-level quantification methods in environmental monitoring and risk assessment is underscored by the results. The risk assessment showed a moderate risk of exposure to the nearby coastal population through the food chain.

Взгляды военно-политического руководства США на защиту критически важных объектов от угроз кибернетического воздействия

The study examines the potential threats of cybernetic impact on critical U.S. facilities that support the activities of the armed forces, and the measures of the American administration to identify and neutralize them. Based on the results of the analysis, it was concluded that the destructive impact on critical infrastructure undermines the military potential of the state and the combat capability of the armed forces. The multidimensional and cross-border nature of threats objectively necessitates the search for ways to prevent and eliminate such threats, as well as the development of interdepartmental and international cooperation in combating cyber threats. This requirement places a burden on state and military leaders to possess knowledge not only in the realm of military security but also in the field of national cybersecurity. Significant cross-industry risks are associated with energy infrastructure, particularly with the supply of gas to electricity producers. The most vulnerable parts of infrastructure are the energy systems that are utilized to supply electricity to military bases and other U.S. military facilities located abroad. A crucial aspect of ensuring the cyber security of energy infrastructure is the regulation of the supply chain for information technology products. Awareness of vulnerabilities within the cybersecurity framework of the U.S. defense infrastructure can be leveraged to refine the list of critical targets of a potential adversary and inform the planning and execution of information operations by the General Staff of the Armed Forces of the Russian Federation.

Resveratrol as a potential therapeutic agent for sarcopenic obesity: Insights from in vivoperiments

Sarcopenic obesity (SO) is a metabolic disorder with increasing prevalence. It is characterized by a reduction in skeletal muscle mass and strength. Resveratrol (RSV) is one of the most frequently used herbs in the treatment of skeletal muscle atrophy. However, the precise mechanism of the action of RSV in SO remains unclear. The objective of this study was to examine the pharmacological mechanism of RSV in the context of SO through the lens of network pharmacology, to validate these findings through in vivo experimentation. A list of potential RSV targets was compiled by retrieving the data from multiple databases. This list was then cross-referenced with a list of potential targets related to SO. The intersections of RSV- and SO-related targets were analyzed using Venn diagrams. To identify the core genes, a protein-protein interaction (PPI) network of the intersection targets was constructed and subsequently analyzed. Molecular docking was used to predict RSV binding to its core targets. A high-fat diet was used to induce SO in mice. These findings indicated that RSV may prevent SO by acting on 11 targets. Among these, interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor (TNF) are considered core targets. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results indicated that the anti-SO effect of RSV was predominantly linked to metabolic disease-related pathways, including those associated with nonalcoholic fatty liver disease. The anti-inflammatory effects of RSV were confirmed in vivo in an SO mouse model. This study contributes to a more comprehensive understanding of the key mechanisms of the action of RSV against SO and provides new possibilities for drug development in the pathological process of SO.

Mycobacterial Targets for Thiourea Derivatives: Opportunities for Virtual Screening in Tuberculosis Drug Discovery.

Tuberculosis (TB) remains a primary global health concern, necessitating the discovery and development of new anti-TB drugs, mainly to combat drug-resistant strains. In this context, thiourea derivatives have emerged as promising candidates in TB drug discovery due to their diverse chemical structures and pharmacological properties. This review aimed to explore this potential, identifying and exploring molecular targets for thiourea derivatives in Mycobacterium tuberculosis (Mtb) and the potential application of virtual screening techniques in drug discovery. We have compiled a comprehensive list of possible molecular targets of thiourea derivatives in Mtb. The enzymes are primarily involved in the biosynthesis of various cell wall components, including mycolic acids, peptidoglycans, and arabinans, or targets in the branched-chain amino acid biosynthesis (BCAA) pathway and detoxification mechanisms. We discuss the potential of these targets as critical constituents for the design of novel anti-TB drugs. Besides, we highlight the opportunities that virtual screening methodologies present in identifying potential thiourea derivatives that can interact with these molecular targets. The presented findings contribute to the ongoing efforts in TB drug discovery and lay the foundation for further research in designing and developing more effective treatments against this devastating disease.

A new perspective on microRNA-guided gene regulation specificity, and its potential generalization to transcription factors and RNA-binding proteins.

Our conception of gene regulation specificity has undergone profound changes over the last 20years. Previously, regulators were considered to control few genes, recognized with exquisite specificity by a 'lock and key' mechanism. However, recentlygenome-wide exploration of regulator binding site occupancy (whether on DNA or RNA targets) revealed extensive lists of molecular targets for every studied regulator. Such poor biochemical specificity suggested that each regulator controls many genes, collectively contributing to biological phenotypes. Here, I propose a third model, whereby regulators' biological specificity is only partially due to 'lock and key' biochemistry. Rather, regulators affect many genes at the microscopic scale, but biological consequences for most interactions are attenuated at the mesoscopic scale: only a few regulatory events propagate from microscopic to macroscopic scale;others are made inconsequential by homeostatic mechanisms. This model is well supported by the microRNA literature, and data suggest that it extends to other regulators. It reconciles contradicting observations from biochemistry and comparative genomics on one hand and in vivo genetics on the other hand, but this conceptual unification is obscured by common misconceptions and counter-intuitive modes of graphical display. Profound understanding of gene regulation requires conceptual clarification, and better suited statistical analyses and graphical representation.

PAX fusion proteins deregulate gene networks controlling mitochondrial translation in pediatric rhabdomyosarcoma.

Alveolar rhabdomyosarcoma (ARMS) patients harboring PAX3-FOXO1 and PAX7-FOXO1 fusion proteins exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood cancer. To uncover mechanisms that contribute to tumor initiation, we developed a novel muscle progenitor model and used epigenomic approaches to unravel genome re-wiring events mediated by PAX3/7 fusion proteins. Importantly, these regulatory mechanisms are conserved across established ARMS cell lines, primary tumors, and orthotopic-patient derived xenografts. Among the key targets of PAX3- and PAX7-fusion proteins, we identified a cohort of oncogenes, FGF receptors, and genes essential for mitochondrial metabolism and protein translation, which we successfully targeted in preclinical trials. Our data suggest an explanation for the relative paucity of recurring mutations in this tumor, provide a compelling list of actionable targets, and suggest promising new strategies to treat this tumor.

A sensitive, expandable AQC-based LC-MS/MS method to measure amino metabolites and sphingolipids in cell and serum samples

Sphingolipids are a major lipid species found in all eukaryotes. Among structurally complex and diversified lipids, sphingoid bases have been heavily linked to various metabolic diseases. However, most current LC-MS-based methods lack the sensitivity to detect low-abundant sphingoid bases. The 6-Aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) derivatization reagent, which efficiently forms covalent bonds with amino groups, has been widely used for amino acid detection. Nevertheless, the commonly used reverse-phase HPLC method for amino acid analysis is not suitable for amphipathic sphingolipids. To address this issue, we report a robust reverse-phase HPLC-MS/MS method capable of separating and detecting hydrophilic amino acids and sphingoid bases in a single run with high sensitivity. This method is also inclusive of other amino metabolites with an expandable target list. We tested this method under various conditions and samples, demonstrating its high reproducibility and sensitivity. Using this approach, we systematically analyzed human serum samples from healthy individuals, dyslipidemia, and type II diabetes mellitus (T2DM) patients, respectively. Two sphingolipids and five amino acids were identified with significant differences between the control and T2DM groups, highlighting the potential of this method in clinical studies.

Seasonal hot spots of pollution and risks in Western Kenya: A spatial-temporal analysis of almost 800 organic micropollutants

The release of chemicals into the environment presents a significant threat to aquatic ecosystems dependent on the proximity to emission sources and seasonal dynamics of emission and mobilization. While spatial-temporal information on water pollution in Europe is increasing, there are substantial knowledge gaps on seasonal pollution dynamics in tropical countries. Thus, we took Lake Victoria South Basin in western Kenya as a case study to identify spatial and seasonal hot spots of contamination, quantified toxic risks to different groups of organisms, and identified seasonal risk drivers. For this purpose, we analyzed grab water samples from five rivers with agricultural and wastewater treatment plants in their catchment in four different seasons. We used liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) with a target list of 785 organic micropollutants. A total of 307 compounds were detected with concentrations ranging from 0.3 ng/L to 6.6 μg/L. Using a Toxic Unit (TU) approach based on mixture toxicity to standard test organisms, crustaceans were identified as the most affected group followed by algae and fish. For crustaceans, chronic risk thresholds were exceeded in 96 % of all the samples, while 56 % of all samples are expected to be acutely toxic, with the highest risk in February during the dry season. High toxic unit values for algae and fish were recorded in July dry season and May wet season. Diazinon, imidacloprid, clothianidin and pirimiphos-methyl were the major drivers for crustacean toxicity while triclosan and different herbicide mixtures drive risks to algae in dry and wet seasons, respectively. A total of 18 chemicals were found to exceed acute and chronic environmental risk thresholds. With this study, strong spatial-temporal patterns of pollution, risks and risk drivers could be confirmed informing prioritization of monitoring and abatement to enhance water quality and reduce toxic risks.

Enhancing invasive alien plant eradication outcomes: Lessons learned from South Africa

AbstractSeveral attempts to eradicate invasive alien species have been initiated in South Africa and despite no formal eradication declaration, several species have been brought down to low levels or are now absent from the country. Based on an expert workshop with South African implementing agencies on best nationwide eradication practices, we recommend that eradication programmes should be well coordinated, and characterised by collaboration between implementing agencies, researchers and practitioners. Countries should have a list of eradication targets informed by the best available science, with targets ranked according to priority. The best eradication model should be used consistently until eradication is achieved. While most of these priority areas are not novel, it does provide a perspective from a biodiverse African country with limited funding, based on 16 years of experience in implementing eradication programmes. It corroborates challenges experienced elsewhere in the world and contributes to enhancing eradication outcomes globally.

Occurrence, removal and risk assessment of chemicals of emerging concern in selected rivers and wastewater treatment plants in western Kenya

Water resources play a crucial role in sustaining life on earth yet chemicals of emerging concern (CECs) arising from extensive human applications are an increasing threat towards their existence. In this study, we examined the occurrence, removal and potential risk of CECs found in rivers and wastewater treatment plants (WWTPs) in western Kenya. Samples were prepared by solid-phase extraction and analysed using high performance liquid chromatography-mass spectrometry with a target list of 785 compounds. Out of these, 333 and 352 (influent 322, effluent 265) compounds were quantified in rivers and wastewater respectively, with pharmaceuticals, industrial compounds, and pesticides being frequently detected in both rivers and WWTPs. Compounds with highest concentrations included saccharin (9.9 μg/L), metformin (7.5 μg/L), and oxypurinol (6.5 μg/L) in rivers whereas caffeine (280 μg/L), deoxycholic acid (179 μg/L), 2-oxindole (10.9 μg/L) and ibuprofen (8.1 μg/L) were found at high concentrations in WWTPs. Based on the types of crops grown, samples from maize growing regions recorded the highest number of pesticides (75) which coincided with the spraying season. The WWTP showed the capacity to eliminate some compounds although the removal efficiencies varied greatly with 204 compounds exhibiting an average removal efficiency exceeding 50 %. Based on the risk assessment, crustaceans had the highest potential risk for toxicity with toxic unit (TU) values up to 5.4 driven primarily by diazinon and dichlorvos followed by algae (TU up to 0.07) and fish (TU up to 0.01) in rivers. A similar trend was observed in WWTP with diazinon (TU up to 5.5), diuron (TU up to 0.07) and carbendazim (TU up to 0.006) driving the risk for crustaceans, algae and fish respectively. These findings highlight the significance of surface water and WWTPs as sources and sinks of CECs in the environment translating to potential risks on aquatic organisms and humans.

Mechanism of drug-pairs Astragalus Mongholicus-Largehead Atractylodes on treating knee osteoarthritis investigated by GEO gene chip with network pharmacology and molecular docking.

Investigations into the therapeutic potential of Astragalus Mongholicus (AM, huáng qí) and Largehead Atractylodes (LA, bái zhú) reveal significant efficacy in mitigating the onset and progression of knee osteoarthritis (KOA), albeit with an elusive mechanistic understanding. This study delineates the primary bioactive constituents and their molecular targets within the AM-LA synergy by harnessing the comprehensive Traditional Chinese Medicine (TCM) network databases, including TCMSP, TCMID, and ETCM. Furthermore, an analysis of 3 gene expression datasets, sourced from the gene expression omnibus database, facilitated the identification of differential genes associated with KOA. Integrating these findings with data from 5 predominant databases yielded a refined list of KOA-associated targets, which were subsequently aligned with the gene signatures corresponding to AM and LA treatment. Through this alignment, specific molecular targets pertinent to the AM-LA therapeutic axis were elucidated. The construction of a protein-protein interaction network, leveraging the shared genetic markers between KOA pathology and AM-LA intervention, enabled the identification of pivotal molecular targets via the topological analysis facilitated by CytoNCA plugins. Subsequent GO and KEGG enrichment analyses fostered the development of a holistic herbal-ingredient-target network and a core target-signal pathway network. Molecular docking techniques were employed to validate the interaction between 5 central molecular targets and their corresponding active compounds within the AM-LA complex. Our findings suggest that the AM-LA combination modulates key biological processes, including cellular activity, reactive oxygen species modification, metabolic regulation, and the activation of systemic immunity. By either augmenting or attenuating crucial signaling pathways, such as MAPK, calcium, and PI3K/AKT pathways, the AM-LA dyad orchestrates a comprehensive regulatory effect on immune-inflammatory responses, cellular proliferation, differentiation, apoptosis, and antioxidant defenses, offering a novel therapeutic avenue for KOA management. This study, underpinned by gene expression omnibus gene chip analyses and network pharmacology, advances our understanding of the molecular underpinnings governing the inhibitory effects of AM and LA on KOA progression, laying the groundwork for future explorations into the active components and mechanistic pathways of TCM in KOA treatment.

Transitions in magnetic behavior at the substellar boundary

We aim to advance our understanding of magnetic activity and the underlying dynamo mechanism at the end of the main sequence. To this end, we have embarked on collecting simultaneous X-ray and radio observations for a sample of M7..L0 dwarfs in the solar neighborhood using XMM-Newton jointly with the Jansky Very Large Array (JVLA) and the Australia Telescope Compact Array (ATCA). We supplemented the data from these dedicated campaigns with X-ray data from the all-sky surveys of the ROentgen Survey with an Imaging Telescope Array (eROSITA) on board the Russian Spektrum-Roentgen-Gamma mission (SRG). Moreover, we complement this multiwavelength data set with rotation periods that we measured from light curves acquired with the Transiting Exoplanet Survey Satellite (TESS). We limited the sample to objects with rotation period of &lt; 1 day, focusing on the study of a transition in magnetic behavior suggested by a drastic change in the radio detection rate at υ sin i ≈ 38 km s−1, corresponding to Prot ≈ 0.2 day for a typical ultracool dwarf (UCD) radius of R★ = 0.15 R⊙. Finally, to enlarge the target list, we have compiled archival X-ray and radio data for UCDs from the literature, and we have analyzed the abovementioned ancillary eROSITA and TESS observations for these objects’ analogous to the targets from our dedicated X-ray/radio campaigns. We compiled the most up to date radio/X-ray luminosity (LR,ν − Lx) relation for 26 UCDs with rotation periods (Prot) lower than 1 day, finding that rapid rotators lie the furthest away from the “Güdel-Benz” relation previously studied for earlier-type stars. Radio bursts are mainly (although not exclusively) experienced by very fast UCDs (Prot ≤ 0.2 day), while X-ray flares are seen by objects spanning the whole range of rotation. Finally, we examined the Lx/Lbol versus Prot relation, where our sample of UCDs spans a large activity level range, that is log(Lx/Lbol) = −5.5 to log(Lx/Lbol) = −3. Although they are all fast rotating, X-ray activity evidently decouples from that of normal dynamos. In fact, we found no evident relation between the X-ray emission and rotation, reinforcing previous speculations on a bimodal dynamo across late-type dwarfs. One radio-detected object, 2MJ0838, has a rotation period consistent with the range of auroral bursting sources; while it displays moderately circularly polarized emission, there is no temporal variation in the polarized flux. A radio flare from this object is interpreted as gyrosynchrotron emission, and it displays X-ray and optical flares. Among the ten UCDs observed with the dedicated X-ray/radio campaigns, we found a slowly rotating apparent auroral emitter (2MJ0752) that is also one of the X-ray brightest radio-detected UCDs. We speculate that this UCD is experiencing a transition in its magnetic behavior since it produces signatures expected from higher-mass M dwarfs along with emerging evidence of auroral emission.

Determining the functional role of the Gluconobacter oxydans GOX1969 protein as a BamB homolog.

Acetic acid bacteria are used in many industrial processes such as the production of vinegar, vitamin C, the antidiabetic drug miglitol, and various artificial flavorings. These industrially important reactions are primarily carried out by an arsenal of periplasmic-facing membrane-bound dehydrogenases that incompletely oxidize their substrates and shuttle electrons directly into the respiratory chain. Among these dehydrogenases, GOX1969 in Gluconobacter oxydans was predicted to be a pyrroloquinoline quinone-dependent dehydrogenase of unknown function. However, after multiple analysis by a number of labs, no dehydrogenase activity has been detected. Reanalysis of GOX1969 sequence and structure reveals similarities to Escherichia coli BamB, which functions as a subunit of the β-barrel assembly machinery complex that is responsible for the assembly of β-barrel outer membrane proteins in Gram-negative bacteria. To test if the physiological function of GOX1969 is similar to BamB in E. coli, we introduced the gox1969 gene into an E. coli ∆bamB mutant. Growth deficiencies in the ∆bamB mutant were restored when gox1969 was expressed on the plasmid pGox1969. Furthermore, increased membrane permeability conferred by bamB deletion was restored upon gox1969 expression, which suggests a direct link between GOX1969 and a role in maintaining outer membrane stability. Together, this evidence strongly suggests that GOX1969 is functionally acting as a BamB in G. oxydans. As such, functional information on uncharacterized genes will provide new insights that will allow for more accurate modeling of acetic acid bacterial metabolism and further efforts to design rational strains for industrial use.IMPORTANCEGluconobacter oxydans is an industrially important member of the acetic acid bacteria. Experimental characterization of putative genes is necessary to identify targets for further engineering of rational acetic acid bacteria strains that can be used in the production of vitamin C, antidiabetic compounds, artificial flavorings, or novel compounds. In this study, we have identified an undefined dehydrogenase GOX1969 with no known substrate and defined structural similarities to outer membrane biogenesis protein BamB in E. coli K12. Furthermore, we demonstrate that GOX1969 is capable of complementing bamB knockout phenotypes in E. coli K12. Taken together, these findings enhance our understanding of G. oxydans physiology and expand the list of potential targets for future industrial strain design.

CFSA: Comparative flux sampling analysis as a guide for strain design

Genome-scale metabolic models of microbial metabolism have extensively been used to guide the design of microbial cell factories, still, many of the available strain design algorithms often fail to produce a reduced list of targets for improved performance that can be implemented and validated in a step-wise manner. We present Comparative Flux Sampling Analysis (CFSA), a strain design method based on the extensive comparison of complete metabolic spaces corresponding to maximal or near-maximal growth and production phenotypes. The comparison is complemented by statistical analysis to identify reactions with altered flux that are suggested as targets for genetic interventions including up-regulations, down-regulations and gene deletions. We applied CFSA to the production of lipids by Cutaneotrichosporon oleaginosus and naringenin by Saccharomyces cerevisiae identifying engineering targets in agreement with previous studies as well as new interventions. CFSA is an easy-to-use, robust method that suggests potential metabolic engineering targets for growth-uncoupled production that can be applied to the design of microbial cell factories.

Differential Analysis of Cereblon Neosubstrates in Rabbit Embryos Using Targeted Proteomics

Targeted protein degradation is the selective removal of a protein of interest through hijacking intracellular protein cleanup machinery. This rapidly growing field currently relies heavily on the use of the E3 ligase cereblon (CRBN) to target proteins for degradation, including the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide which work through a molecular glue mechanism of action with CRBN. While CRBN recruitment can result in degradation of a specific protein of interest (e.g., efficacy), degradation of other proteins (called CRBN neosubstrates) also occurs. Degradation of one or more of these CRBN neosubstrates is believed to play an important role in thalidomide-related developmental toxicity observed in rabbits and primates. We identified a set of 25 proteins of interest associated with CRBN-related protein homeostasis and/or embryo/fetal development. We developed a targeted assay for these proteins combining peptide immunoaffinity enrichment and high-resolution mass spectrometry and successfully applied this assay to rabbit embryo samples from pregnant rabbits dosed with three IMiDs. We confirmed previously reported in vivo decreases in neosubstrates like SALL4, as well as provided evidence of neosubstrate changes for proteins only examined in vitro previously. While there were many proteins that were similarly decreased by all three IMiDs, no compound had the exact same neosubstrate degradation profile as another. We compared our data to previous literature reports of IMiD-induced degradation and known developmental biology associations. Based on our observations, we recommend monitoring at least a major subset of these neosubstrates in a developmental test system to improve CRBN-binding compound-specific risk assessment. A strength of our assay is that it is configurable, and the target list can be readily adapted to focus on only a subset of proteins of interest or expanded to incorporate new findings as additional information about CRBN biology is discovered.