Construction of an efficient Claviceps paspali cell factory for lysergic acid production

Lysergic acid (LA) is the key precursor of ergot alkaloids, and its derivatives have been used extensively for the treatment of neurological disorders. However, the poor fermentation efficiency limited its industrial application. At the same time, the hardship of genetic manipulation has hindered the metabolic engineering of Claviceps strains to improve the LA titer further. In this study, an efficient genetic manipulation system based on the protoplast-mediated transformation was established in the industrial strain Claviceps paspali. On this basis, the gene lpsB located in the ergot alkaloids biosynthetic gene cluster was deleted to construct the LA-producing cell factory. Plackett-Burman and Box-Behnken designs were used in shaking flasks, achieving an optimal fermentation medium composition. The final titer of LA and iso-lysergic acid (ILA) reached 3.7 g·L−1, which was 4.6 times higher than that in the initial medium. Our work provides an efficient strategy for the biosynthesis of LA and ILA and lays the groundwork for its industrial production

Solar Ring Mission: Building a Panorama of the Sun and Inner-heliosphere

Solar Ring (SOR) is a proposed space science mission to monitor and study the Sun and inner heliosphere from a full 360{\deg} perspective in the ecliptic plane. It will deploy three 120{\deg}-separated spacecraft on the 1-AU orbit. The first spacecraft, S1, locates 30{\deg} upstream of the Earth, the second, S2, 90{\deg} downstream, and the third, S3, completes the configuration. This design with necessary science instruments, e.g., the Doppler-velocity and vector magnetic field imager, wide-angle coronagraph, and in-situ instruments, will allow us to establish many unprecedented capabilities: (1) provide simultaneous Doppler-velocity observations of the whole solar surface to understand the deep interior, (2) provide vector magnetograms of the whole photosphere - the inner boundary of the solar atmosphere and heliosphere, (3) provide the information of the whole lifetime evolution of solar featured structures, and (4) provide the whole view of solar transients and space weather in the inner heliosphere. With these capabilities, Solar Ring mission aims to address outstanding questions about the origin of solar cycle, the origin of solar eruptions and the origin of extreme space weather events. The successful accomplishment of the mission will construct a panorama of the Sun and inner-heliosphere, and therefore advance our understanding of the star and the space environment that holds our life.Comment: 41 pages, 6 figures, 1 table, to be published in Advances in Space Researc

Negative regulation of floral transition in Arabidopsis by HOS15-PWR-HDA9 complex

Arabidopsis HOS15/PWR/HDA9 repressor complex, which is similar to the TBL1/NcoR1/HDAC complex in animals, plays a well-known role in epigenetic regulation. PWR and HDA9 have been reported to interact with each other and modulate the flowering time by repressing AGL19 expression, whereas HOS15 and HDA9, together with the photoperiodic evening complex, regulate flowering time through repression of GI transcription. However, the role of the HOS15/PWR/HDA9 core repressor complex as a functional unit in the regulation of flowering time is yet to be explored. In this study, we reported that the loss-of-function hos15-2/pwr/hda9 triple mutant accumulates higher transcript levels of AGL19 and exhibits an early flowering phenotype similar to those of hos15, pwr, and hda9 single mutants. Interestingly, the accumulation of HOS15 in the nucleus was drastically reduced in pwr and hda9 mutants. As a result, HOS15 could not perform its role in histone deacetylation or interaction with H3 in the nucleus. Furthermore, HOS15 is also associated with the same region of the AGL19 promoter known for PWR-HDA9 binding. The acetylation level of the AGL19 promoter was increased in the hos15-2 mutant, similar to the pwr and hda9 mutants. Therefore, our findings reveal that the HOS15/PWR/HDA9 repressor complex deacetylates the promoter region of AGL19, thereby negatively regulating AGL19 transcription, which leads to early flowering in Arabidopsis

Pain Chemogenomics Knowledgebase (PAIN-CKB) for Systems Pharmacology Target Mapping and PBPK Modeling Investigation of Opioid Drug-Drug Interactions

More than 50 million adults in America suffer from chronic pain. Opioids are commonly prescribed for their effectiveness in relieving many types of pain. However, excessive prescribing of opioids can lead to abuse, addiction, and death. Non-steroidal anti-inflammatory drugs (NSAIDs), another major class of analgesic, also have many problematic side effects including headache, dizziness, vomiting, diarrhea, nausea, constipation, reduced appetite, and drowsiness. There is an urgent need for the understanding of molecular mechanisms that underlie drug abuse and addiction to aid in the design of new preventive or therapeutic agents for pain management. To facilitate pain related small-molecule signaling pathway studies and the prediction of potential therapeutic target(s) for the treatment of pain, here we present a comprehensive platform of pain domain-specific chemogenomics knowledgebase (PAIN-CKB) with integrated data mining computing tools. Our new computing platform describes the chemical molecules, genes, proteins, and signaling pathways involved in pain regulation. PAIN-CKB is implemented with a friendly user-interface for the prediction of the relevant protein targets of the query compound and analysis and visualization of the outputs based on HTDocking, TargetHunter, BBB predictor, and Spider Plot. We performed three case studies to systematically validate the integrity and accuracy of PAIN-CKB and its algorithms/tools. First, system pharmacology target mapping was carried out for four FDA approved analgesics (acetaminophen, diclofenac, fentanyl, and morphine) in order to identify the known targets and predict off-targets. Subsequently, the target mapping outcomes were applied to build physiologically based pharmacokinetic (PBPK) models for acetaminophen and fentanyl to explore the potential drug-drug interaction (DDI) between this pair of drugs. Finally, docking analysis was conducted to explore the detailed interaction pattern of acetaminophen reactive metabolite (NAPQI) and its hepatotoxicity target thioredoxin reductase (TrxR)

Evaluation of Tourism Development Efficiency and Spatial Spillover Effect Based on EBM Model: The Case of Hainan Island, China

Tourism development efficiency is one of the key scales to measure the development quality of tourism destination. This study improves the existing input–output index system of tourism efficiency evaluation; knowledge innovation is introduced into the input index, and environmental health pressure is introduced into the output index. Based on the case of Hainan Island, we used the EBM model compatible with radial and non-radial data to evaluate the tourism development efficiency. In order to make up the deficiency of spatial effect analysis based on the geographical distance weight matrix, the spatial spillover effect of tourism development in Hainan Island was analyzed based on a geographical distance weight matrix and an economic distance weight matrix. The findings indicate that nearly 20 years of the Hainan tourism development efficiency mean value was 0.7435, represented by Sanya, and Haikou city of Hainan’s tourism industry development level was higher. However, the spatial spillover effect of Hainan’s overall tourism development is not good. In addition to Tunchang, Ledong city suggests that an appropriate increase in tourism elements, such as investment, expands the scale of the tourism industry, and most cities follow the law of diminishing marginal utility and inappropriate scale blindly. Especially in the face of knowledge innovation becoming the main factor hindering the efficiency of tourism development, we should pay more attention to technological innovation and management reform and coordinate the relationship between tourism development and ecological environment protection

Regulated Disorder: Posttranslational Modifications Control the RIN4 Plant Immune Signaling Hub.

RIN4 is an intensively studied immune regulator in Arabidopsis and is involved in perception of microbial features outside and bacterial effectors inside plant cells. Furthermore, RIN4 is conserved in land plants and is targeted for posttranslational modifications by several virulence proteins from the bacterial pathogen Pseudomonas syringae. Despite the important roles of RIN4 in plant immune responses, its molecular function is not known. RIN4 is an intrinsically disordered protein (IDP), except at regions where pathogen-induced posttranslational modifications take place. IDP act as hubs for protein complex formation due to their ability to bind to multiple client proteins and, thus, are important players in signal transduction pathways. RIN4 is known to associate with multiple proteins involved in immunity, likely acting as an immune-signaling hub for the formation of distinct protein complexes. Genetically, RIN4 is a negative regulator of immunity, but diverse posttranslational modifications can either enhance its negative regulatory function or, on the contrary, render it a potent immune activator. In this review, we describe the structural domains of RIN4 proteins, their intrinsically disordered regions, posttranslational modifications, and highlight the implications that these features have on RIN4 function. In addition, we will discuss the potential role of plasma membrane subdomains in mediating RIN4 protein complex formations

Cross-Layer Federated Learning Optimization in MIMO Networks

In this paper, the performance optimization of federated learning (FL), when deployed over a realistic wireless multiple-input multiple-output (MIMO) communication system with digital modulation and over-the-air computation (AirComp) is studied. In particular, an MIMO system is considered in which edge devices transmit their local FL models (trained using their locally collected data) to a parameter server (PS) using beamforming to maximize the number of devices scheduled for transmission. The PS, acting as a central controller, generates a global FL model using the received local FL models and broadcasts it back to all devices. Due to the limited bandwidth in a wireless network, AirComp is adopted to enable efficient wireless data aggregation. However, fading of wireless channels can produce aggregate distortions in an AirComp-based FL scheme. To tackle this challenge, we propose a modified federated averaging (FedAvg) algorithm that combines digital modulation with AirComp to mitigate wireless fading while ensuring the communication efficiency. This is achieved by a joint transmit and receive beamforming design, which is formulated as a optimization problem to dynamically adjust the beamforming matrices based on current FL model parameters so as to minimize the transmitting error and ensure the FL performance. To achieve this goal, we first analytically characterize how the beamforming matrices affect the performance of the FedAvg in different iterations. Based on this relationship, an artificial neural network (ANN) is used to estimate the local FL models of all devices and adjust the beamforming matrices at the PS for future model transmission. The algorithmic advantages and improved performance of the proposed methodologies are demonstrated through extensive numerical experiments

The Style-Content Duality of Attractiveness: Learning to Write Eye-Catching Headlines via Disentanglement

Eye-catching headlines function as the first device to trigger more clicks, bringing reciprocal effect between producers and viewers. Producers can obtain more traffic and profits, and readers can have access to outstanding articles. When generating attractive headlines, it is important to not only capture the attractive content but also follow an eye-catching writtenstyle. In this paper, we propose a Disentanglement-based Attractive Headline Generator (DAHG) that generates headline which captures the attractive content following the attractive style. Concretely, we first devise a disentanglement module to divide the style and content of an attractive prototype headline into latent spaces, with two auxiliary constraints to ensure the two spaces are indeed disentangled. The latent content information is then used to further polish the document representation and help capture the salient part. Finally, the generator takes the polished document as input to generate headline under the guidance of the attractive style. Extensive experiments on the public Kuaibao dataset show that DAHG achieves state-of-the-art performance. Human evaluation also demonstrates that DAHG triggers 22% more clicks than existing models

The Pseudomonas syringae type III effectors AvrRpm1 and AvrRpt2 promote virulence dependent on the F-box protein COI1

Key message: Type III effectors AvrRpm1 and AvrRpt2 promote bacterial growth dependent on a COI1-mediated pathway in the absence of the RPM1 and RPS2 resistance proteins. Abstract: The type III effectors, AvrRpm1 and AvrRpt2, promote bacterial virulence by suppressing host defense responses. The defense suppressing activities of AvrRpm1 and AvrRpt2 are best studied in the absence of the resistance proteins RPM1 and RPS2, which induce defense responses to them. We tested whether the type III effectors could modulate a CORONATINE INSENSITIVE1 (COI1)-mediated hormone signaling pathway to promote virulence. COI1 has been demonstrated to contribute in the induction of chlorosis during Pseudomonas syringae infection. By comparing the activity of inducibly expressed AvrRpm1-HA or AvrRpt2-HA in rpm1rps2 and rpm1rps2coi1 backgrounds, we demonstrate that both effectors promote bacterial growth dependent on a COI1-mediated pathway and additively with the action of coronatine (COR) and that AvrRpt2-HA induces COI1-dependent chlorosis. Further, PATHOGENESIS RELATED1 (PR-1) expression resulting from inducible expression of AvrRpm1-HA or AvrRpt2-HA is elevated in coi1 plants consistent with the effectors activating JA-signaling to antagonize SA-signaling. In addition, we found that AvrRpm1-HA or AvrRpt2-HA requires COI1 to promote bacterial growth through suppression of both SA-dependent and SA-independent defense responses. Collectively, these results indicate that type III effectors AvrRpm1 and AvrRpt2 promote bacterial virulence by targeting a COI1-dependent signaling pathway. © 2016, Springer-Verlag Berlin Heidelberg.