3D printing of interferon γ-preconditioned NSC-derived exosomes/collagen/chitosan biological scaffolds for neurological recovery after TBI.

The reconstruction of neural function and recovery of chronic damage following traumatic brain injury (TBI) remain significant clinical challenges. Exosomes derived from neural stem cells (NSCs) offer various benefits in TBI treatment. Numerous studies confirmed that appropriate preconditioning methods enhanced the targeted efficacy of exosome therapy. Interferon-gamma (IFN-γ) possesses immunomodulatory capabilities and is widely involved in neurological disorders. In this study, IFN-γ was employed for preconditioning NSCs to enhance the efficacy of exosome (IFN-Exo, IE) for TBI. miRNA sequencing revealed the potential of IFN-Exo in promoting neural differentiation and modulating inflammatory responses. Through low-temperature 3D printing, IFN-Exo was combined with collagen/chitosan (3D-CC-IE) to preserve the biological activity of the exosome. The delivery of exosomes via biomaterial scaffolds benefited the retention and therapeutic potential of exosomes, ensuring that they could exert long-term effects at the injury site. The 3D-CC-IE scaffold exhibited excellent biocompatibility and mechanical properties. Subsequently, 3D-CC-IE scaffold significantly improved impaired motor and cognitive functions after TBI in rat. Histological results showed that 3D-CC-IE scaffold markedly facilitated the reconstruction of damaged neural tissue and promoted endogenous neurogenesis. Further mechanistic validation suggested that IFN-Exo alleviated neuroinflammation by modulating the MAPK/mTOR signaling pathway. In summary, the results of this study indicated that 3D-CC-IE scaffold engaged in long-term pathophysiological processes, fostering neural function recovery after TBI, offering a promising regenerative therapy avenue.

Low-intensity ultrasound ameliorates brain organoid integration and rescues microcephaly deficits.

Human brain organoids represent a remarkable platform for modeling neurological disorders and a promising brain repair approach. However, the effects of physical stimulation on their development and integration remain unclear. Here, we report that low-intensity ultrasound significantly increases neural progenitor cell proliferation and neuronal maturation in cortical organoids. Histological assays and single-cell gene expression analyses reveal that low-intensity ultrasound improves the neural development in cortical organoids. Following organoid grafts transplantation into the injured somatosensory cortices of adult mice, longitudinal electrophysiological recordings and histological assays reveal that ultrasound-treated organoid grafts undergo advanced maturation. They also exhibit enhanced pain-related gamma-band activity and more disseminated projections into the host brain than the untreated groups. Finally, low-intensity ultrasound ameliorates neuropathological deficits in a microcephaly brain organoid model. Hence, low-intensity ultrasound stimulation advances the development and integration of brain organoids, providing a strategy for treating neurodevelopmental disorders and repairing cortical damage.

Relation-Aware Heterogeneous Graph Network for Learning Intermodal Semantics in Textbook Question Answering.

Textbook question answering (TQA) task aims to infer answers for given questions from a multimodal context, including text and diagrams. The existing studies have aggregated intramodal semantics extracted from a single modality but have yet to capture the intermodal semantics between different modalities. A major challenge in learning intermodal semantics is maintaining lossless intramodal semantics while bridging the gap of semantics caused by heterogeneity. In this article, we propose an intermodal relation-aware heterogeneous graph network (IMR-HGN) to extract the intermodal semantics for TQA, which aggregates different modalities while learning features rather than representing them independently. First, we design a multidomain consistent representation (MDCR) to eliminate semantic gaps by capturing intermodal features while maintaining lossless intramodal semantics in multidomains. Furthermore, we present neighbor-based relation inpainting (NRI) to reduce semantic ambiguity via repairing fuzzy relations with correlations of relations. Finally, we propose hierarchical multisemantics aggregation (HMSA) to guarantee the completeness of semantics by aggregating features of nodes and relations with a reconstruction network (RN). Experimental results show that IMR-HGN could extract the intermodal semantics of answers, achieving a 2.16% improvement on the validation set of the TQA dataset and a 3.04% increase on the test set of the AI2D dataset.

Synthesis of 3-Phenylserine by a Two-enzyme Cascade System with PLP Cofactor.

A two-enzyme cascade system containing ω-transaminase (ω-TA) and L-threonine aldolase (L-ThA) was reported for the synthesis of 3-Phenylserine starting from benzylamine, and PLP was utilized as the only cofactor in these both two enzymes reaction system. Based on the transamination results, benzylamine was optimized as an advantageous amino donor as confirmed by MD simulation results. This cascade reaction system could not only facilitate the in situ removal of the co-product benzaldehyde, enhancing the economic viability of the reaction, but also establish a novel pathway for synthesizing high-value phenyl-serine derivatives. In our study, nearly 95 % of benzylamine was converted, yielding over 54 % of 3-Phenylserine under the optimized conditions cascade reaction.

Nonstructural protein VP2 of chicken anemia virus triggers IFN-ß expression via host cGAS.

Chicken anemia virus (CAV) constitutes an important economic threat for the poultry industry. Advancing the understanding of the pathogenic process of CAV infection, we had previously demonstrated that CAV VP1 has the ability to inhibit expression of IFN-ß via cGAS-STING signalling pathway. Here to go further to reveal this regulatory role of viral phosphatase VP2, we have performed protein-protein interaction assays with cGAS adaptors, as well as IFN-ß induction screenings. Contrary to VP1, VP2 of CAV stimulates the expression of IFN-ß, a regulatory effect more closely associated with cGAS (in the context of the cGAS-STING axis) than with STING, TBK1 or IRF7. The results reported here offer new insights about the molecular mechanisms that varied viral proteins act in a timely manner on the host during CAV infection.

Cooperative chemoenzymatic synthesis of N-heterocycles via synergizing bio- with organocatalysis.

Inspired by Nature's ingenuity, considerable progress has been made in recent years to develop chemoenzymatic processes by the integration of environmentally friendly feature of biocatalysis with versatile reactivity of chemocatalysis. However, the current types of chemoenzymatic processes are relatively few and mostly rely on metal catalysts. Here, we report a previously unexplored cooperative chemoenzymatic system for the synthesis of N-heterocycles. Starting from alcohols and amines, benzimidazole, pyrazine, quinazoline, indole, and quinoline can be obtained in excellent yields in water with O2 as the terminal oxidant. Synthetic bridged flavin analog is served as a bifunctional organocatalyst for the regeneration of cofactor nicotinamide adenine dinucleotide in the bioprocess and oxidative cyclodehydrogenation in the chemoprocess. Compared to the classical acceptorless dehydrogenative coupling strategy, being metal and base free, requiring only water as solvent, and not needing atmosphere protection were observed for the present method, exhibiting a favorable green and sustainable alternative.

Constructing a multienzyme cascade redox-neutral system for the synthesis of halogenated indoles.

Inspired by biocatalytic retrosynthesis, a multienzyme cascade system containing alcohol dehydrogenase, flavin-dependent halogenase and flavin reductase was developed for the synthesis of several halogenated indoles starting from amino alcohol. This redox-neutral system not only omitted co-substrate for nicotinamide cofactor (NADH) regeneration but also showed relatively higher conversion and chemoselectivity compared with individual biotransformation. Artificial nicotinamide cofactor (BNAH) was employed to replace NADH and flavin reductase for simplifying this system, providing a more convenient strategy for halogenated indoles.

Biosynthesis of lactones from diols mediated by an artificial flavin.

BACKGROUND: Lactones are important compounds in the field of medicine, material and chemical industry. One of the promising accesses to these flexible scaffolds is NAD(P)+-dependent alcohol dehydrogenases-catalyzed oxidative lactonization of diols, which relies on the construction of an efficient NAD(P)+ regeneration system. RESULTS: In this study, a novel system combining horse liver alcohol dehydrogenase (HLADH) with the synthetic bridged flavin cofactor was established for biosynthesis of lactones. The reaction conditions of this system were optimized and a variety of lactones including chiral lactones were efficiently obtained from various diols. Compared to the previously reported NAD(P)+-regeneration systems, this system showed better regeneration efficiency and product yield. A two-phase system was further applied to solve the problem of product inhibition, and 80% yield was obtained at the condition of 300 mM substrate. CONCLUSIONS: This study provides an efficient method to synthesis of lactones from diols under mild conditions. We believe this system will be a promising alternative to promote the synthesis of other valuable compounds.

Factors affecting the mortality of patients with COVID-19 undergoing surgery and the safety of medical staff: A systematic review and meta-analysis.

BACKGROUND: The 2019 novel coronavirus disease (COVID-19) can complicate the perioperative course to increase postoperative mortality in operative patients, and also is a serious threat to medical staff. However, studies summarizing the impact of COVID-19 on the perioperative mortality of patients and on the safety of medical staff are lacking. METHODS: We searched PubMed, Cochrane Library, Embase and Chinese database National Knowledge Infrastructure (CNKI) with the search terms "COVID-19″ or "SARS-CoV-2″ and "Surgery" or "Operation" for all published articles on COVID-19 from December 1, 2019 to October 5, 2020. FINDINGS: A total of 269 patients from 47 studies were included in our meta-analysis. The mean age of operative patients with COVID-19 was 50.91 years, and 49% were female. A total of 28 patients were deceased, with the overall mortality of 6%. All deceased patients had postoperative complications associated with operation or COVID-19, including respiratory failure, acute respiratory distress syndrome (ARDS), short of breath, dyspnea, fever, cough, fatigue or myalgia, cardiopulmonary system, shock/infection, acute kidney injury and severe lymphopenia. Patients who presented any or more of the symptoms of respiratory failure, ARDS, short of breath and dyspnea after operation were associated with significantly higher mortality (r = 0.891, p < 0.001), while patients whose symptoms were presented as fever, cough, fatigue or myalgia only demonstrated marginally significant association with postoperative mortality (r = 0.675, p = 0.023). Twenty studies reported the information of medical staff infection, and a total of 38 medical staff were infected, and medical staff who used biosafety level 3 (BSL-3) protective equipment did not get infected. INTERPRETATION: COVID-19 patients, in particular those with severe respiratory complications, may have high postoperative mortality. Medical staff in close contact with infected patients is suggested to take high level personal protective equipment (PPE). FUNDING: Heilongjiang postdoctoral scientific research developmental fund and the National Natural Science Foundation of China.

Regulating Cofactor Balance In Vivo with a Synthetic Flavin Analogue.

A novel strategy to regulate cofactor balance in vivo for whole-cell biotransformation using a synthetic flavin analogue is reported. High efficiency, easy operation, and good applicability were observed for this system. Confocal laser scanning microscopy was employed to verify that the synthetic flavin analogue can directly permeate into Escherichia coli cells without modifying the cell membrane. This work provides a promising intracellular redox regulatory approach to construct more efficient cell factories.

Minimally inconsistent reasoning in Semantic Web.

Reasoning with inconsistencies is an important issue for Semantic Web as imperfect information is unavoidable in real applications. For this, different paraconsistent approaches, due to their capacity to draw as nontrivial conclusions by tolerating inconsistencies, have been proposed to reason with inconsistent description logic knowledge bases. However, existing paraconsistent approaches are often criticized for being too skeptical. To this end, this paper presents a non-monotonic paraconsistent version of description logic reasoning, called minimally inconsistent reasoning, where inconsistencies tolerated in the reasoning are minimized so that more reasonable conclusions can be inferred. Some desirable properties are studied, which shows that the new semantics inherits advantages of both non-monotonic reasoning and paraconsistent reasoning. A complete and sound tableau-based algorithm, called multi-valued tableaux, is developed to capture the minimally inconsistent reasoning. In fact, the tableaux algorithm is designed, as a framework for multi-valued DL, to allow for different underlying paraconsistent semantics, with the mere difference in the clash conditions. Finally, the complexity of minimally inconsistent description logic reasoning is shown on the same level as the (classical) description logic reasoning.