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Valanimycin is an azoxy‐containing natural product isolated from the fermentation broth of Streptomyces viridifaciens MG456‐hF10. While the biosynthesis of valanimycin has been partially characterized, how the azoxy group is constructed remains obscure. Herein, the membrane protein VlmO and the putative hydrazine synthetase ForJ from the formycin biosynthetic pathway are demonstrated to catalyze N−N bond formation converting O‐(l‐seryl)‐isobutyl hydroxylamine into N‐(isobutylamino)‐l‐serine. Subsequent installation of the azoxy group is shown to be catalyzed by the non‐heme diiron enzyme VlmB in a reaction in which the N−N single bond in the VlmO/ForJ product is oxidized by four electrons to yield the azoxy group. The catalytic cycle of VlmB appears to begin with a resting μ‐oxo diferric complex in VlmB, as supported by Mössbauer spectroscopy. This study also identifies N‐(isobutylamino)‐d‐serine as an alternative substrate for VlmB leading to two azoxy regioisomers. The reactions catalyzed by the kinase VlmJ and the lyase VlmK during the final steps of valanimycin biosynthesis are established as well. The biosynthesis of valanimycin was thus fully reconstituted in vitro using the enzymes VlmO/ForJ, VlmB, VlmJ and VlmK. Importantly, the VlmB‐catalyzed reaction represents the first example of enzyme‐catalyzed azoxy formation and is expected to proceed by an atypical mechanism. [ABSTRACT FROM AUTHOR]

We show how one can test the cosmological Poisson equation by requiring only the validity of three main assumptions: the energy-momentum conservation equations of matter, the equivalence principle, and the cosmological principle. We first point out that one can only measure the combination M ≡ Ω m (0) μ , where μ quantifies the deviation of the Poisson equation from the standard one and Ω m (0) is the fraction of matter density at present. Then we employ a recent model-independent forecast for the growth rate f (z) and the expansion rate E (z) to obtain constraints on M for a survey that approximates a combination of the Dark Energy Spectroscopic Instrument (DESI) and Euclid. We conclude that a constant M can be measured with a relative error σ M = 4.5 % , while if M is arbitrarily varying in redshift, it can be measured only to within 13.4% (1 σ c.l.) at redshift z = 0.9 , and 15-22% up to z = 1.5. We also project our constraints on some parametrizations of M proposed in literature, while still maintaining model-independence for the background expansion, the power spectrum shape, and the non-linear corrections. Generally speaking, as expected, we find much weaker model-independent constraints than found so far for such models. This means that the cosmological Poisson equation remains quite open to various alternative gravity and dark energy models. [ABSTRACT FROM AUTHOR]

After spinal cord injury (SCI), phagocytes endocytose myelin debris to form foam cells, exacerbating the inflammatory response. It has been previously shown that macrophages become foam cells through the phagocytosis of myelin debris via receptor-dependent mechanisms after SCI. Blocking receptor-mediated endocytosis did not completely prevent foam cell formation, so we investigated receptor-independent endocytosis. Here, we revealed that foam cells formed after myelin debris internalization were predominantly macrophages rather than microglia. Receptor-independent macropinocytosis has an important position in foamy macrophage formation through engagement of myelin debris endocytosis after SCI. Mechanistic studies showed that cholesterol crystallization following macropinocytosis-mediated foamy macrophage formation promoted the reactive oxygen species (ROS) production and the NOD-like receptor protein 3 (NLRP3) inflammasome activation, increasing the secretion of interleukin-1β (IL-1β). Inhibition of macropinocytosis might reverse this effect, resulting in enhanced axonal regeneration and reduced neural apoptosis, thereby improving outcomes after SCI. Overall, our study revealed a previously unrecognized role for macropinocytosis in foamy macrophages formation after SCI, and confer a promising therapeutic strategy for SCI through focus on macropinocytosis., Competing Interests: Declaration of competing interest The author declares no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Kitasetaline is one of the very few β-carbolines isolated from bacteria. It features a unique N -acetylcysteine moiety linked to the β-carboline core through a thioether bond. While earlier in vivo experiments identified the gene cluster and reported several putative biosynthetic intermediates, how the C-S bond linkage is constructed has remained elusive. Herein, in vitro reconstitution of kitasetaline biosynthesis reveals the involvement of a Pictet-Spenglerase (KslB) and a promiscuous dehydrogenase (KslA) that generate the characteristic β-carboline ring system. In addition, the P450 enzyme KslC was found to catalyze oxidative decarboxylation of 1-(2-carboxyethyl)-9 H -pyrido[3,4- b ]indole-3-carboxylic acid to yield the biosynthetic intermediate 1-vinyl-9 H -pyrido[3,4- b ]indole-3-carboxylic acid. KslC is also capable of catalyzing further oxidation of its product to yield an N -hydroxylated side product. Importantly, the vinyl intermediate was found to undergo nonenzymatic nucleophilic addition by N -acetyl-l-cysteine to generate the C-S bond leading directly to kitasetaline without the involvement of a mycothiolated intermediate proposed in a previous biosynthetic model. Thus, this work not only demonstrates that biosynthesis of β-carboline compounds is rich in unexpected chemistry but also adds to the growing realization that biological thiolation reactions are often nonenzymatic in nature, relying instead on enzymatic formation of reactive electrophiles.

Transcrestal maxillary sinus floor elevation is an effective method to solve the problem of insufficient bone height in the posterior maxillary region. However, current methods, such as osteotome sinus floor elevation, cushioned grind-out technique, Smart Drill technique, etc., require specialized surgical tool boxes. In this article, we introduce a new method of transcrestal maxillary sinus elevation that uses built-in reamers of various implant systems to scrap residual bone at the sinus floor and uses the implant to push the sinus membrane during implant placement. This technique is easy to operate and time saving and has a low rate of sinus membrane perforation. After a one-year follow-up observation of 146 people and 175 implants, the endo-sinus bone gains were 5.00 (4.70, 5.30) mm and 2.10 (1.40, 2.70) mm in the group of 3 mm≤residual bone height (RBH)<5 mm and the group of 5 mm≤RBH<8 mm, respectively, which can meet the clinical requirements of implant stability. This technique is suitable in generalizing dental implantation.

Federated learning (FL) commonly encourages the clients to perform multiple local updates before the global aggregation, thus avoiding frequent model exchanges and relieving the communication bottleneck between the server and clients. Though empirically effective, the negative impact of multiple local updates on the stability of FL is not thoroughly studied, which may result in a globally unstable and slow convergence. Based on sensitivity analysis, we define in this paper a local-update stability index for the general FL, as measured by the maximum inter-client model discrepancy after the multiple local updates that mainly stems from the data heterogeneity. It enables to determine how much the variation of client's models with multiple local updates may influence the global model, and can also be linked with the convergence and generalization. We theoretically derive the proposed local-update stability for current state-of-the-art FL methods, providing possible insight to understanding their motivation and limitation from a new perspective of stability. For example, naively executing the parallel acceleration locally at clients would harm the local-update stability. Motivated by this, we then propose a novel accelerated yet stabilized FL algorithm (named FedANAG) based on the server- and client-level Nesterov accelerated gradient (NAG). In FedANAG, the global and local momenta are elaborately designed and alternatively updated, while the stability of local update is enhanced with help of the global momentum. We prove the convergence of FedANAG for strongly convex, general convex and non-convex settings. We then conduct evaluations on both the synthetic and real-world datasets to first validate our proposed local-update stability. The results further show that across various data heterogeneity and client participation ratios, FedANAG not only accelerates the global convergence by reducing the required number of communication rounds to a target accuracy, but converges to an eventually higher accuracy.

Objectives: This study aims to compare the accuracy of self-developed universal implant guide (SDG), 3D printed digital guide (DG), and free hand (FH) simulated implantation in the posterior tooth area of dental models., Methods: Ten junior dentists were selected to place three implants in the 35, 37, and 46 tooth sites of the mandibular models (35, 36, 37, and 46 missing teeth) by using SDG, DG, and FH, and the process was repeated again to take the average value. Cone beam computed tomography (CBCT) was used to evaluate the global coronal deviation, global apical deviation, depth deviation, and angular deviation between the actual position and preoperative planned position., Results: The coronal deviation and apical deviation of the three implant sites in the SDG group were not significantly different from those in the two other groups ( P >0.05). The depth deviation and angular deviation in the SDG group were smaller than those in the DG group ( P <0.05) and FH group ( P <0.05), respectively. All deviations at site 37 in the SDG group were not different from those at site 35 ( P >0.05), while the depth and angular deviation at site 37 in the DG group were higher than those at site 35 ( P <0.05)., Conclusions: The precision of the self-developed universal dental implant guide can meet the requirements of clinical posterior implantation.

Objective: Dissolving microneedles (DMNs) have shown great potential for transdermal drug delivery due to their excellent skin-penetrating ability and combination with nanocarriers (NCs) can realize targeted drug delivery. The objective of this study was to investigate the impact of microneedle dissolving rate on the in vivo fate of NC-loaded DMNs, which would facilitate the clinical translation of such systems., Methods: Solid lipid nanoparticles (SLNs) were selected as the model NC for loading in DMNs, which were labeled by P4 probes with aggregation-quenching properties. Sodium hyaluronate acid (HA) and chitosan (CS), with different aqueous dissolving rates, were chosen as model tip materials. The effects of needle dissolving rate on the in vivo fate of NC-loaded DMNs was investigated by tracking the distribution of fluorescence signals after transdermal exposure., Results: P4 SLNs achieved a deeper diffusion depth of 180 μm in DMN-HA with a faster dissolution rate, while the diffusion depth in DMN-CS with a slower dissolution rate was lower (140 μm). The in vivo experiments demonstrated that P4 SLNs had a T 1/2 value of 12.14 h in DMN-HA, whilst a longer retention time was found in DMN-CS, with a T 1/2 of 13.12 h., Conclusions: This study confirmed that the in vivo diffusion rate of NC-loaded DMNs was determined by the dissolving rate of DMNs materials and provided valuable guidance for the design and development of NC-loaded DMNs in the future.