Search

Glycosylation is a ubiquitous modification present across all of biology, affecting many things such as physicochemical properties, cellular recognition, subcellular localization, and immunogenicity. Nucleotide sugars are important precursors needed to study glycosylation and produce glycosylated products. Saccharomyces cerevisiae is a potentially powerful platform for producing glycosylated biomolecules, but it lacks nucleotide sugar diversity. Nucleotide sugar metabolism is complex, and understanding how to engineer it will be necessary to both access and study heterologous glycosylations found across biology. This review overviews the potential challenges with engineering nucleotide sugar metabolism in yeast from the salvage pathways that convert free sugars to their associated UDP-sugars to de novo synthesis where nucleotide sugars are interconverted through a complex metabolic network with governing feedback mechanisms. Finally, recent examples of engineering complex glycosylation of small molecules in S. cerevisiae are explored and assessed.

QS-21 is a potent vaccine adjuvant and remains the only saponin-based adjuvant that has been clinically approved for use in humans1,2. However, owing to the complex structure of QS-21, its availability is limited. Today, the supply depends on laborious extraction from the Chilean soapbark tree or on low-yielding total chemical synthesis3,4. Here we demonstrate the complete biosynthesis of QS-21 and its precursors, as well as structural derivatives, in engineered yeast strains. The successful biosynthesis in yeast requires fine-tuning of the host's native pathway fluxes, as well as the functional and balanced expression of 38 heterologous enzymes. The required biosynthetic pathway spans seven enzyme families-a terpene synthase, P450s, nucleotide sugar synthases, glycosyltransferases, a coenzyme A ligase, acyl transferases and polyketide synthases-from six organisms, and mimics in yeast the subcellular compartmentalization of plants from the endoplasmic reticulum membrane to the cytosol. Finally, by taking advantage of the promiscuity of certain pathway enzymes, we produced structural analogues of QS-21 using this biosynthetic platform. This microbial production scheme will allow for the future establishment of a structure-activity relationship, and will thus enable the rational design of potent vaccine adjuvants.

Valerolactam is a monomer used to manufacture high-value nylon-5 and nylon-6,5. However, the biological production of valerolactam has been limited by the inadequate efficiency of enzymes to cyclize 5-aminovaleric acid to produce valerolactam. In this study, we engineered Corynebacterium glutamicum with a valerolactam biosynthetic pathway consisting of DavAB from Pseudomonas putida to convert L-lysine to 5-aminovaleric acid and β-alanine CoA transferase (Act) from Clostridium propionicum to produce valerolactam from 5-aminovaleric acid. Most of the L-lysine was converted into 5-aminovaleric acid, but promoter optimization and increasing the copy number of Act were insufficient to significantly improve the titer of valerolactam. To eliminate the bottleneck at Act, we designed a dynamic upregulation system (a positive feedback loop based on the valerolactam biosensor ChnR/Pb). We used laboratory evolution to engineer ChnR/Pb to have higher sensitivity and a higher dynamic output range, and the engineered ChnR-B1/Pb-E1 system was used to overexpress the rate-limiting enzymes (Act/ORF26/CaiC) that cyclize 5-aminovaleric acid into valerolactam. In glucose fed-batch culture, we obtained 12.33 g/L valerolactam from the dynamic upregulation of Act, 11.88 g/L using ORF26, and 12.15 g/L using CaiC. Our engineered biosensor (ChnR-B1/Pb-E1 system) was also sensitive to 0.01-100 mM caprolactam, which suggests that this dynamic upregulation system can be used to enhance caprolactam biosynthesis in the future.

Increases in temperature and pressure caused by rapid burial of sediments seaward of the Sumatra subduction zone have been hypothesized to trigger dehydration reactions that diagenetically strengthen sediments and contribute to the formation of an over‐pressured pre‐décollement, which together facilitate the occurrence of large shallow earthquakes. We present paleomagnetic, rock magnetic, and electron microscopic analyses from drill cores collected offshore Sumatra at Site U1480 during IODP Expedition 362 that support this hypothesis. The older pre‐fan units (Late Cretaceous to early Paleocene) were deposited when Site U1480 was moving rapidly northward with the Indian plate from a paleolatitude of 50° to 30°S, which would equate to expected absolute paleomagnetic inclinations of 70°–43°. Most of the older pre‐fan sediments, however, have shallow observed inclinations (shallower than ±20°), indicating that the sediments were overprinted when Site U1480 was located near the paleoequator, as it has been since the early Oligocene. Electron microscopic observations reveal that the pre‐existing detrital magnetite grains have undergone pervasive dissolution and alteration by hydrothermal fluids. The diagenesis observed is consistent with mineral dehydration, possibly driven by rapid burial of pelagic sediments by the ∼1250 m thick Nicobar Fan sequence. In addition, the elevated burial temperature also facilitated the smectite to illite conversion reaction. We hypothesize that chemical reactions resulted in the formation of fine‐grained magnetite that records a chemical remanent magnetization overprint. This overprint is consistent with the alteration occurring after burial by the thick Nicobar Fan sequence sometime in the past few million years. Plain Language Summary: Sediments and rocks commonly contain magnetic minerals that record the direction and intensity of Earth's magnetic field as they are being emplaced, thus preserving an ancient record of the geomagnetic field. Subsequent alteration of the magnetic minerals caused by heating and/or fluid circulation can result in the acquisition of secondary magnetizations (i.e., remagnetization) that may overprint or completely reset the primary ancient magnetization. Such remagnetization provides evidence of the physical and chemical changes that have occurred. Here through paleomagnetic, rock magnetic, and microscopic analyses of the deeper older (pre‐fan) stratigraphic sequence cored offshore Sumatra, we find that hydrothermal fluids, resulting from mineral dehydration driven by rapid burial of this sequence by younger, thick Nicobar Fan sediments, led to pervasive secondary remagnetization. Consequently, the newly formed magnetite recorded a much younger paleomagnetic field, leaving a shallow overprint that probably occurred sometime in the past few million years. The dehydration reactions also increased the strength of the sediments entering the subduction zone and aided in the formation of slip surfaces (called décollements), possibly contributing to the shallow, large earthquakes that have generated tsunamis off Sumatra. Key Points: The 60–67 Ma pre‐fan sediments offshore Sumatra were most likely remagnetized since deposition of the Nicobar Fan sediments, which began at ∼9 MaRemagnetization of pre‐fan sediments caused by mineral dehydration may be linked to shallow seismogenic slip off SumatraMagnetic properties of input sediments in the subduction margin record conditions that may have facilitated the generation of earthquakes [ABSTRACT FROM AUTHOR]

Fungi-mediated synthesis of Gold nanoparticles (AuNPs) has advantages in: high efficiency, low energy consumption, no need for extra capping and stabilizing agents, simple operation, and easy isolation and purification. Many fungi have been found to synthesize AuNPs inside cells or outside cells, providing different composition and properties of particles when different fungi species or reaction conditions are used. This is good to produce AuNPs with different properties, but may cause challenges to precisely control the particle shape, size, and activities. Besides, low concentrations of substrate and fungal biomass are needed to synthesize small-size particles, limiting the yield of AuNPs in a large scale. To find clues for the development methods to solve these challenges, the reported mechanisms of the fungi-mediated synthesis of AuNPs were summarized. The mechanisms of intracellular AuNPs synthesis are dependent on gold ions absorption by the fungal cell wall via proteins, polysaccharides, or electric absorption, and the reduction of gold ions via enzymes, proteins, and other cytoplasmic redox mediators in the cytoplasm or cell wall. The extracellular synthesis of AuNPs is mainly due to the metabolites outside fungal cells, including proteins, peptides, enzymes, and phenolic metabolites. These mechanisms cause the great diversity of the produced AuNPs in functional groups, element composition, shapes, sizes, and properties. Many methods have been developed to improve the synthesis efficiency by changing: chloroauric acid concentrations, reaction temperature, pH, fungal mass, and reaction time. However, future studies are still required to precisely control the: shape, size, composition, and properties of fungal AuNPs. [ABSTRACT FROM AUTHOR]

The application of digital technologies is the core driving force for innovating traditional development and realizing a leap in productivity. The innovative development governance of the Yellow River Basin is a complex social system, involving economic, social, and ecological aspects. Its key driving force is the profound influence of digital technologies. Focused on how digital technologies empower the innovative development governance of the Yellow River Basin, the development process, problems, and challenges are analyzed at different stages, from the digital Yellow River to the digital twin Yellow River. It is found that the governance of the Yellow River Basin still requires enhancement in four aspects: building a digital innovation ecosystem, establishing a digital governance system, developing data infrastructure, and preventing data security risks. In order to address these challenges so as to promote the realization of the innovative development goals of the Yellow River Basin, four policy recommendations are proposed, namely, encouraging a scientific and technological innovation ecology, improving the agile digital governance system, strengthening the practical value and application of innovations, and enhancing the digital security barrier capacity. [ABSTRACT FROM AUTHOR]

Purpose: To summarize and analyze the safety and efficacy of a Y-shape Sigma stent loaded with I125 in patients with inoperable malignant main airway obstruction. Methods: This study was approved by the Institutional Ethics Committee, and a written informed consent was obtained from each participant. A Y-shape Sigma stent loaded with I125 was placed under vision from rigid bronchoscopy. The primary endpoint was alleviation of symptoms and improvement of Karnofsky Performance Status (KPS) score, and the secondary endpoint was complications and technical success. Results: From November 2018 through June 2023, total 33 patients with malignant airway obstruction were palliatively treated by installing Y-shape Sigma stents loaded with I125. The airway lumen was immediately restored and the average airway opening significantly increased to 70 ± 9.4% after the procedure from baseline 30.2 ± 10.5% (p < 0.05). Average KPS score was improved from baseline 30.0 ± 10.0 to 70.0 ± 10.0 (p < 0.05) as well as PaO2 from baseline 50.1 ± 15.4 mmHg to 89.3 ± 8.6 mmHg (p < 0.05). The technical success rate of placing the stent in this study was 73%, and adverse events or complications including bleeding, I125 loss, and airway infection occurred during or after the procedure. Conclusion: Placement of Y-shape Sigma stents under vision from rigid bronchoscopy in the patients with malignant airway obstruction is feasible and it immediately alleviates dyspnea and significantly improves quality of life. [ABSTRACT FROM AUTHOR]