Beyond generative models: superfast traversal,optimization, novelty,exploration and discovery (STONED) algorithm for molecules using SELFIES

Inverse design allows the generation of molecules with desirable physical quantities using property optimization. Deep generative models have recently been applied to tackle inverse design, as they possess the ability to optimize molecular properties directly through structure modification using gradients. While the ability to carry out direct property optimizations is promising, the use of generative deep learning models to solve practical problems requires large amounts of data and is very time-consuming. In this work, we propose STONED – a simple and efficient algorithm to perform interpolation and exploration in the chemical space, comparable to deep generative models. STONED bypasses the need for large amounts of data and training times by using string modifications in the SELFIES molecular representation. First, we achieve non-trivial performance on typical benchmarks for generative models without any training. Additionally, we demonstrate applications in high-throughput virtual screening for the design of drugs, photovoltaics, and the construction of chemical paths, allowing for both property and structure-based interpolation in the chemical space. Overall, we anticipate our results to be a stepping stone for developing more sophisticated inverse design models and benchmarking tools, ultimately helping generative models achieve wider adoption.

Interpolation and exploration within the chemical space for inverse design.     

白藜芦醇的合成新方法

本文探索了合成白藜芦醇的新方法。以3,5-二甲氧基苯胺为原料,经重氮化、还原及乙酰化得到中间体N′-乙酰基-3,5-二甲氧基苯肼(4),中间体4与4-甲氧基苯乙烯经Mizoroki-Heck偶联反应得中间体5,脱去甲基即得到目标产物白藜芦醇,总收率约31.9%。中间体及目标产物的结构均经质谱及核磁氢谱确证。该路线操作简便、条件温和,可用于白藜芦醇的放大制备。     

Local immune cell contributions to fracture healing in aged individuals – A novel role for interleukin 22

With increasing age, the risk of bone fractures increases while regenerative capacity decreases. This variation in healing potential appears to be linked to adaptive immunity, but the underlying mechanism is still unknown. This study sheds light on immunoaging/inflammaging, which impacts regenerative processes in aging individuals. In an aged preclinical model system, different levels of immunoaging were analyzed to identify key factors that connect immunoaged/inflammaged conditions with bone formation after long bone fracture. Immunological facets, progenitor cells, the microbiome, and confounders were monitored locally at the injury site and systemically in relation to healing outcomes in 12-month-old mice with distinct individual levels of immunoaging. Bone tissue formation during healing was delayed in the immunoaged group and could be associated with significant changes in cytokine levels. A prolonged and amplified pro-inflammatory reaction was caused by upregulated immune cell activation markers, increased chemokine receptor availability and a lack of inhibitory signaling. In immunoaged mice, interleukin-22 was identified as a core cell signaling protein that played a central role in delayed healing. Therapeutic neutralization of IL-22 reversed this specific immunoaging-related disturbed healing. Immunoaging was found to be an influencing factor of decreased regenerative capacity in aged individuals. Furthermore, a novel therapeutic strategy of neutralizing IL-22 may successfully rejuvenate healing in individuals with advanced immune experiences.Subject terms: Trauma, Mechanisms of disease, Interleukins, Osteoimmunology     

A Comparative Loading and Release Study of Vancomycin from a Green Mesoporous Silica

Since its first use as a drug delivery system, mesoporous silica has proven to be a surprisingly efficient vehicle due to its porous structure. Unfortunately, most synthesis methods are based on using large amounts of surfactants, which are then removed by solvent extraction or heat treatment, leading to an undesired environmental impact because of the generated by-products. Hence, in the present study, we followed the synthesis of a silica material with a wormhole-like pore arrangement, using two FDA-approved substances as templates, namely Tween-20 and starch. As far as we know, it is the first study using the Tween-20/starch combo as a template for mesoporous silica synthesis. Furthermore, we investigated whether the obtained material using this novel synthesis had any potential in using it as a DDS. The material was further analyzed by XRD, TEM, FT-IR, N₂ adsorption/desorption, and DLS to investigate its physicochemical features. Vancomycin was selected as the active molecule based on the extensive research engaged towards improving its bioavailability for oral delivery. The drug was loaded onto the material by using three different approaches, assuming its full retention in the final system. Thermal analysis confirmed the successful loading of vancomycin by all means, and pore volume significantly decreased upon loading, especially in the case of the vacuum-assisted method. All methods showed a slower release rate compared to the same amount of the pure drug. Loadings by physical mixing and solvent evaporation released the whole amount of the drug in 140 min, and the material loaded by the vacuum-assisted method released only 68.2% over the same period of time, leading us to conclude that vancomycin was adsorbed deeper inside the pores. The kinetic release of the three systems followed the Higuchi model for the samples loaded by physical mixing and vacuum-assisted procedures, while the solvent evaporation loading method was in compliance with the first-order model.     

Reduction of Weed Growth under the Influence of Extracts and Metabolites Isolated from Miconia spp.

Weeds pose a problem, infesting areas and imposing competition and harvesting difficulties in agricultural systems. Studies that provide the use of alternative methods for weed control, in order to minimize negative impacts on the environment, have intensified. Native flora represents a source of unexplored metabolites with multiple applications, such as bioherbicides. Therefore, we aimed to carry out a preliminary phytochemical analysis of crude extracts and fractions of Miconia auricoma and M. ligustroides and to evaluate these and the isolated metabolites phytotoxicity on the growth of the target species. The growth bioassays were conducted with Petri dishes with lettuce, morning glory, and sourgrass seeds incubated in germination chambers. Phytochemical analysis revealed the presence of flavonoids, isolated myricetin, and a mixture of quercetin and myricetin. The results showed that seedling growth was affected in a dose-dependent manner, with the root most affected and the seedlings of the lettuce, morning glory, and sourgrass as the most sensitive species, respectively. Chloroform fractions and myricetin were the most inhibitory bioassays evaluated. The seedlings showed structural changes, such as yellowing, nonexpanded cotyledons, and less branched roots. These results indicate the phytotoxic potential of Miconia allelochemicals, since there was the appearance of abnormal seedlings and growth reduction.     

Melatonin: A Neurotrophic Factor?

Melatonin, N-acetyl-5-hydroxytryptamine, is a hormone that synchronizes the internal environment with the photoperiod. It is synthesized in the pineal gland and greatly depends on the endogenous circadian clock located in the suprachiasmatic nucleus and the retina’s exposure to different light intensities. Among its most studied functions are the regulation of the waking-sleep rhythm and body temperature. Furthermore, melatonin has pleiotropic actions, which affect, for instance, the modulation of the immune and the cardiovascular systems, as well as the neuroprotection achieved by scavenging free radicals. Recent research has supported that melatonin contributes to neuronal survival, proliferation, and differentiation, such as dendritogenesis and axogenesis, and its processes are similar to those caused by Nerve Growth Factor, Brain-Derived Neurotrophic Factor, Neurotrophin-3, and Neurotrophin-4/5. Furthermore, this indolamine has apoptotic and anti-inflammatory actions in specific brain regions akin to those exerted by neurotrophic factors. This review presents evidence suggesting melatonin’s role as a neurotrophic factor, describes the signaling pathways involved in these processes, and, lastly, highlights the therapeutic implications involved.     

Synthesis and Characterization of New Ruthenium (II) Complexes of Stoichiometry [Ru(p-Cymene)Cl2L] and Their Cytotoxicity against HeLa-Type Cancer Cells

When the [Ru(p-cymene)(μ-Cl)Cl]₂ complex is made to react, in dichloromethane, with the following ligands: 2-aminobenzonitrile (2abn), 4-aminobenzonitrile (4abn), 2-aminopyridine (2ampy) and 4-aminopyridine (4ampy), after addition of hexane, the following compounds are obtained: [Ru(p-cymene)Cl₂(2abn)] (I), [Ru(p-cymene)Cl₂(4abn)] (II), [Ru(p-cymene)Cl₂(2ampy] (III) and [Ru(p-cymene)Cl₂(μ-(4ampy)] (IV). All the compounds are characterized by elemental analysis of carbon, hydrogen and nitrogen, proton nuclear magnetic resonance, COSY ¹H-¹H, high-resolution mass spectrometry (ESI), thermogravimetry and single-crystal X-ray diffraction (the crystal structure of III is reported and compared with the closely related literature of II). The cytotoxicity effects of complexes were described for cervical cancer HeLa cells via 3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide (MTT) assay. The results demonstrate a low in vitro anticancer potential of the complexes.     

Lycopene,Mesoporous Silica Nanoparticles and Their Association: A Possible Alternative against Vulvovaginal Candidiasis?

Commonly found colonizing the human microbiota, Candida albicans is a microorganism known for its ability to cause infections, mainly in the vulvovaginal region known as vulvovaginal candidiasis (VVC). This pathology is, in fact, one of the main C. albicans clinical manifestations, changing from a colonizer to a pathogen. The increase in VVC cases and limited antifungal therapy make C. albicans an increasingly frequent risk in women’s lives, especially in immunocompromised patients, pregnant women and the elderly. Therefore, it is necessary to develop new therapeutic options, especially those involving natural products associated with nanotechnology, such as lycopene and mesoporous silica nanoparticles. From this perspective, this study sought to assess whether lycopene, mesoporous silica nanoparticles and their combination would be an attractive product for the treatment of this serious disease through microbiological in vitro tests and acute toxicity tests in an alternative in vivo model of Galleria mellonella. Although they did not show desirable antifungal activity for VVC therapy, the present study strongly encourages the use of mesoporous silica nanoparticles impregnated with lycopene for the treatment of other human pathologies, since the products evaluated here did not show toxicity in the in vivo test performed, being therefore, a topic to be further explored.     

Enantioselective Hydrogenation of Endocyclic Enones:the Solution to a Historical Problem

The enantioselective hydrogenation of endocyclic enones has been a historical problem for homogeneous catalysis.We herein report an efficient method to reduce e...     

Inhibition of Bacterial Adhesion and Biofilm Formation by Seed-Derived Ethanol Extracts from Persea americana Mill

The increase in antibiotic resistance demands innovative strategies to combat microorganisms. The current study evaluated the antibacterial and antivirulence effects of ethanol extracts from Persea americana seeds obtained by the Soxhlet (SE) and maceration (MaE) methods. The UHPLC-DAD-QTOF analysis showed mainly the presence of polyphenols and neolignan. Ethanol extracts were not cytotoxic to mammalian cells (CC₅₀ > 500 µg/mL) and displayed a moderate antibacterial activity against Pseudomonas aeruginosa (IC₅₀ = 87 and 187 µg/mL) and Staphylococcus aureus (IC₅₀ = 144 and 159 µg/mL). Interestingly, no antibacterial activity was found against Escherichia coli. SE and MaE extracts were also able to significantly reduce the bacterial adhesion to A549 lung epithelial cells. Additionally, both extracts inhibited the biofilm growth at 24 h and facilitated the release of internal cell components in P. aeruginosa, which might be associated with cell membrane destabilization. Real-time PCR and agarose electrophoresis gel analysis indicated that avocado seed ethanol extracts (64 µg/mL) downregulated virulence-related factors such as mexT and lasA genes. Our results support the potential of bioproducts from P. americana seeds as anti-adhesive and anti-biofilm agents.