Identification of genes essential for fluorination and sulfamylation within the nucleocidin gene clusters of Streptomyces calvus and Streptomyces virens

We thank the EPSRC, Leverhulme Trust (RPG-2021-028) and the EU Horizon 2020 Sinfonia consortia for financial support. The Chinese Scholarship Council is acknowledged for studentship support (YC).The gene cluster in Streptomyces calvus associated with the biosynthesis of the fluoro- and sulfamyl-metabolite nucleocidin was interrogated by systematic gene knockouts. Out of the 26 gene deletions most did not affect fluorometabolite production, nine abolished sulfamylation but not fluorination, and three precluded fluorination, having no effect on sulfamylation. In addition to nucI, nucG, nucJ, nucK, nucL, nucN, nucO, nucQ and nucP we identified two genes (nucW, nucA), belonging to a phosphoadenosine phosphosulfate (PAPS) gene cluster, as required for sulfamyl assembly. Three genes (orf(-3), orf2 and orf3) were found to be essential for fluorination, although the activities of their protein products are unknown. These genes as well as nucK, nucN, nucO and nucPNP, whose knockouts produced results differing from those described in a recent report, were also deleted in Streptomyces virens - with confirmatory outcomes. This genetic profile should inform biochemistry aimed at uncovering the enzymology behind nucleocidin biosynthesis.Publisher PDFPeer reviewe

Functionally distinct and selectively phosphorylated GPCR subpopulations co-exist in a single cell.

G protein-coupled receptors (GPCRs) transduce pleiotropic intracellular signals in a broad range of physiological responses and disease states. Activated GPCRs can undergo agonist-induced phosphorylation by G protein receptor kinases (GRKs) and second messenger-dependent protein kinases such as protein kinase A (PKA). Here, we characterize spatially segregated subpopulations of β2-adrenergic receptor (β2AR) undergoing selective phosphorylation by GRKs or PKA in a single cell. GRKs primarily label monomeric β2ARs that undergo endocytosis, whereas PKA modifies dimeric β2ARs that remain at the cell surface. In hippocampal neurons, PKA-phosphorylated β2ARs are enriched in dendrites, whereas GRK-phosphorylated β2ARs accumulate in soma, being excluded from dendrites in a neuron maturation-dependent manner. Moreover, we show that PKA-phosphorylated β2ARs are necessary to augment the activity of L-type calcium channel. Collectively, these findings provide evidence that functionally distinct subpopulations of this prototypical GPCR exist in a single cell

Design, synthesis, and biological activity of novel heptacyclic pyrazolamide derivatives : a new candidate of dual-target insect growth regulators

Insect growth regulators (IGRs) can cause abnormal growth and development in insects, resulting in incomplete metamorphosis or even death of the larvae. Ecdysone receptor (EcR) and chitinase in insects play indispensable roles in the molting process. Ecdysone analogues and chitinase inhibitors are considered as potential IGRs. In order to find new and highly effective IGR candidates, based on the structure-activity relationship and molecular docking results of the active compound 6i (3-(tert-butyl)-N-(4-(tert-butyl)phenyl)-1-phenyl-1H-pyrazole-5-carboxamide) discovered in our previous work, we changed the t-butyl group on the pyrazole ring into heptacycle to enhance the hydrophobicity. Consequently, a series of novel heptacyclic pyrazolamide derivatives were designed and synthesized. The bioassay results demonstrated that some compounds showed obvious insecticidal activity. Especially, D-27 (N-(4-(tert-butyl)phenyl)-2-phenyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-5-carboxamide) showed good activities against Plutella xylostella (LC50, 51.50 mg.L-1) and Mythimna separata (100% mortality at 2.5 mg.L-1). Furthermore, protein validation indicated that D-27 acts not only on the EcR but also on chitinase Of ChtI. Molecular docking and molecular dynamics simulation explained the vital factors in the interaction between D-27 and receptors. D-27 may be a new lead candidate with a dual target in which Of ChtI shall be the main one. This work created a new starting point for discovering a novel type of IGRs

The role of sea spray in air-sea fluxes during Typhoon Molave: a study based on drifting buoy observations

The exchange of heat and momentum between the ocean and the atmosphere greatly affects the growth of typhoons. Utilizing the meteorological and oceanic variables observed by a Drifting Air-sea Interface Buoy (DrIB) during Typhoon Molave, a new air-sea turbulent fluxes product (referred to as DrIB product) is developed with the consideration of the thermal and dynamic effects of sea spray in the Coupled Ocean Atmosphere Response Experiment algorithm. The performances of two reanalysis products, ERA5 and MERRA2, under typhoon conditions are evaluated by comparing them to the DrIB observations. In particular, the air-sea turbulent fluxes during Typhoon Molave are systematically studied. The averaged heat (momentum) flux of the DrIB product is ~200% (~30%) higher than the reanalysis. However, the reanalysis products have higher latent heat than the DrIB product, because the reanalysis products have lower wind speed, smaller air-sea temperature difference, and drier atmosphere. The sea spray-induced mean heat (momentum) flux increase is ~1% (8%) in normal weather and is ~5% (17%) at the during-typhoon stage. Sea spray amplifies the dominance of wind speed on heat fluxes and weakens the contribution of air-sea temperature and humidity differences to heat fluxes. Sea spray starts to obviously contribute to the heat fluxes at a 10-m wind speed of ~10 m/s, and it non-linearly accelerates the air-sea heat exchange at a 10-m wind speed of ~20 m/s. When the 10-m wind speed is less than 20 m/s, the basic momentum flux (without sea spray effects) at the air-sea interface is roughly one or two orders of magnitude higher than the sea spray-induced momentum flux. Including the sea spray effects, the maximum momentum flux can even double at the 10-m wind speed of ~30 m/s

Metagenomic Next-Generation Sequencing in the Diagnosis of HHV-1 Reactivation in a Critically Ill COVID-19 Patient: A Case Report

Background: Secondary infections pose tremendous challenges in Coronavirus disease 2019 (COVID-19) treatment and are associated with higher mortality rates. Clinicians face of the challenge of diagnosing viral infections because of low sensitivity of available laboratory tests. Case Presentation: A 66-year-old woman initially manifested fever and shortness of breath. She was diagnosed as critically ill with COVID-19 using quantitative reverse transcription PCR (RT-qPCR) and treated with antiviral therapy, ventilator and extracorporeal membrane oxygenation (ECMO). However, after the condition was relatively stabled for a few days, the patient deteriorated with fever, frequent cough, increased airway secretions, and increased exudative lesions in the lower right lung on chest X-rays, showing the possibility of a newly acquired infection, though sputum bacterial and fungal cultures and smears showed negative results. Using metagenomic next-generation sequencing (mNGS), we identified a reactivation of latent human herpes virus type 1 (HHV-1) in the respiratory tract, blood and gastrointestinal tract, resulting in a worsened clinical course in a critically ill COVID-19 patient on ECMO. Anti-HHV-1 therapy guided by these sequencing results effectively decreased HHV-1 levels, and improved the patient\u27s clinical condition. After 49 days on ECMO and 67 days on the ventilator, the 66-year-old patient recovered and was discharged. Conclusions: This case report demonstrates the potential value of mNGS for evidence-based treatment, and suggests that potential reactivation of latent viruses should be considered in critically ill COVID-19 patients

Therapeutic Implications of PPAR γ

Osteosarcoma (OS) is the most common nonhematologic malignancy of bone in children and adults. Although dysregulation of tumor suppressor genes and oncogenes, such as Rb, p53, and the genes critical to cell cycle control, genetic stability, and apoptosis have been identified in OS, consensus genetic changes that lead to OS development are poorly understood. Disruption of the osteogenic differentiation pathway may be at least in part responsible for OS tumorigenesis. Current OS management involves chemotherapy and surgery. Peroxisome proliferator-activated receptor (PPAR) agonists and/or retinoids can inhibit OS proliferation and induce apoptosis and may inhibit OS growth by promoting osteoblastic terminal differentiation. Thus, safe and effective PPAR agonists and/or retinoid derivatives can be then used as adjuvant therapeutic drugs for OS therapy. Furthermore, these agents have the potential to be used as chemopreventive agents for the OS patients who undergo the resection of the primary bone tumors in order to prevent local recurrence and/or distal pulmonary metastasis

Skapa en emotionellt positiv upplevelse genom sentimentklassificering för rekommendationssystem för sociala medier : En fallstudie i TikTok

Recommendation system benefits social media by attracting users with the posts they prefer. The recommended posts, however, may not align with what users really need to browse, especially in terms of emotion. Thus we conducted a case study in TikTok, in order to understand the emotional impact of social application’s post feed and to explore the interactive solution. The state-of-arts were reviewed, on the topics of psychology issues caused by social media, related therapy and product solutions. To empathise with users’ situation, a workshop was performed, consisting of a card game, presentation and participatory design. Then an emotion reminder, built on a Naive Bayesian text classifier and a facial expression SVM, was prototyped. With an accuracy of 0.51 (text) and 0.69 (facial expression) in sentiment classification, the emotion reminder was then tested by the users. It was discovered that users had higher emotion awareness, higher sense of control over the browsing and lower engagement in the interface with the prototype, compared with the original TikTok interface. And this was aligned with their needs described in the workshop. Users preferred the prototype’s content-based emotion detection than the detection based on their biological data in terms of privacy, and embraced the format of the reminder, instead of auto-filter, as an emotionally positive experience was not just browsing the posts with positive feelings, but receiving negative posts as well.Rekommendationssystem gynnar sociala medier genom att locka användare med de inlägg de föredrar. De rekommenderade inläggen kan dock inte alltid överensstämma med det användarna verkligen behöver bläddra igenom, särskilt när det gäller känslor. Därför genomförde vi en fallstudie på TikTok för att förstå den emotionella påverkan av sociala applikationers inläggflöde och för att utforska interaktiva lösningar. Den senaste forskningen inom området granskades med fokus på psykologiska problem orsakade av sociala medier, relaterad terapi och produktlösningar. För att sätta oss in i användarnas situation genomfördes en workshop med ett kortspel, presentation och deltagande design. Därefter skapades en känslomässig påminnelse, baserad på en Naive Bayes-textklassificerare och en SVM för ansiktsuttryck. Med en noggrannhet på 0,51 (text) och 0,69 (ansiktsuttryck) i känslolägesklassificering testades sedan känslominnaren av användarna. Det visade sig att användarna hade ökad medvetenhet om sina känslor, ökad känsla av kontroll över bläddrandet och lägre engagemang i gränssnittet med prototypen jämfört med det ursprungliga TikTok-gränssnittet. Detta stämde överens med deras behov som beskrevs under workshopen. Användarna föredrog prototypens innehållsbaserade känslodetektion jämfört med detektering baserad på deras biologiska data av integritetsskäl och omfamnade formatet på påminnelsen istället för automatisk filtrering. En emotionellt positiv upplevelse handlade inte bara om att bläddra bland inlägg med positiva känslor, utan även att ta emot negativa inlägg

Skapa en emotionellt positiv upplevelse genom sentimentklassificering för rekommendationssystem för sociala medier : En fallstudie i TikTok

Recommendation system benefits social media by attracting users with the posts they prefer. The recommended posts, however, may not align with what users really need to browse, especially in terms of emotion. Thus we conducted a case study in TikTok, in order to understand the emotional impact of social application’s post feed and to explore the interactive solution. The state-of-arts were reviewed, on the topics of psychology issues caused by social media, related therapy and product solutions. To empathise with users’ situation, a workshop was performed, consisting of a card game, presentation and participatory design. Then an emotion reminder, built on a Naive Bayesian text classifier and a facial expression SVM, was prototyped. With an accuracy of 0.51 (text) and 0.69 (facial expression) in sentiment classification, the emotion reminder was then tested by the users. It was discovered that users had higher emotion awareness, higher sense of control over the browsing and lower engagement in the interface with the prototype, compared with the original TikTok interface. And this was aligned with their needs described in the workshop. Users preferred the prototype’s content-based emotion detection than the detection based on their biological data in terms of privacy, and embraced the format of the reminder, instead of auto-filter, as an emotionally positive experience was not just browsing the posts with positive feelings, but receiving negative posts as well.Rekommendationssystem gynnar sociala medier genom att locka användare med de inlägg de föredrar. De rekommenderade inläggen kan dock inte alltid överensstämma med det användarna verkligen behöver bläddra igenom, särskilt när det gäller känslor. Därför genomförde vi en fallstudie på TikTok för att förstå den emotionella påverkan av sociala applikationers inläggflöde och för att utforska interaktiva lösningar. Den senaste forskningen inom området granskades med fokus på psykologiska problem orsakade av sociala medier, relaterad terapi och produktlösningar. För att sätta oss in i användarnas situation genomfördes en workshop med ett kortspel, presentation och deltagande design. Därefter skapades en känslomässig påminnelse, baserad på en Naive Bayes-textklassificerare och en SVM för ansiktsuttryck. Med en noggrannhet på 0,51 (text) och 0,69 (ansiktsuttryck) i känslolägesklassificering testades sedan känslominnaren av användarna. Det visade sig att användarna hade ökad medvetenhet om sina känslor, ökad känsla av kontroll över bläddrandet och lägre engagemang i gränssnittet med prototypen jämfört med det ursprungliga TikTok-gränssnittet. Detta stämde överens med deras behov som beskrevs under workshopen. Användarna föredrog prototypens innehållsbaserade känslodetektion jämfört med detektering baserad på deras biologiska data av integritetsskäl och omfamnade formatet på påminnelsen istället för automatisk filtrering. En emotionellt positiv upplevelse handlade inte bara om att bläddra bland inlägg med positiva känslor, utan även att ta emot negativa inlägg

Scalable Compiler for TERMES Distributed Assembly System

The TERMES system is a robot collective capable of autonomously constructing user-specified structures in three dimensions. The compiler is one of the key components that convert the goal structure into a directed map which an arbitrary number of robots can follow to perform decentralized construction. In previous work, the compiler was limited to brute force search which scales poorly with the size of structure. The purpose of this research is to enhance the scalability of the compiler so that it can be applied to very large-scale structures. Correspondingly, a new scalable compiler is presented, with the ability to generate directed maps for structures with up to 1 million stack of bricks. We further recast the old compiler as a constraint satisfaction problem and compare their performance on a range of structures. Results show that the new compiler has significant advantages over the old compiler as the size and complexity of the structures increase. We further developed an automated scheme for improving the transition probability between neighboring stack of bricks for efficient construction. This work represents an important step towards real-world deployment of robot collectives for construction