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To control the development of resistance to conventional insecticides acting as γ-aminobutyric acid (GABA) receptor antagonists (e.g., fipronil), new GABAergic 5,5-disubstituted 4,5-dihydropyrazolo[1,5-a]quinazolines were designed via a scaffold-hopping strategy and synthesized with a facile method. Among the 50 target compounds obtained, compounds 5a, 5b, 7a, and 7g showed excellent insecticidal activities against a susceptible strain of Plutella xylostella (LC50 values ranging from 1.03 to 1.44 μg/mL), which were superior to that of fipronil (LC50 = 3.02 μg/mL). Remarkably, the insecticidal activity of compound 5a was 64-fold better than that of fipronil against the field population of fipronil-resistant P. xylostella. Electrophysiological studies against the housefly GABA receptor heterologously expressed in Xenopus oocytes indicated that compound 5a could act as a potent GABA receptor antagonist, and IC50 was calculated to be 32.5 nM. Molecular docking showed that the binding poses of compound 5a with the housefly GABA receptor can be different compared to fipronil, which explains the effectiveness of compound 5a against fipronil-resistant insects. These findings have suggested compound 5a as a lead compound for a novel GABA receptor antagonist controlling field-resistant insects and provided a basis for further design, structural modification, and development of 4,5-dihydropyrazolo[1,5-a]quinazoline motifs as new insecticidal GABA receptor antagonists.Artesunate is a safe noncytotoxic drug with low side effects which is used in the treatment of chloroquine-resistant malaria. In addition to being an antimalarial drug, artesunate also has immunomodulatory, anticarcinogenic, and antiviral activity. There are in vivo and in vitro studies reporting that artesunate may have a positive effect on the treatment of COVID-19. Artesunate may be effective based on its effect on the anti-inflammatory activity, chloroquine-like endocytosis inhibition mechanism, and nuclear factor kappa B (NF-κB) signal pathway. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause neurological complications in addition to targeting the respiratory system. In this study, we have discussed the possible neuroprotective action mechanisms of artesunate. We think that systemic and intranasal topical artesunate administration may have a positive effect on neurological complications resulting from COVID-19.Pyridoxal kinases (PLK) are crucial enzymes for the biosynthesis of pyridoxal phosphate, an important cofactor in a plethora of enzymatic reactions. The evolution of these enzymes resulted in different catalytic designs. selleck kinase inhibitor In addition to the active site, the importance of a cysteine, embedded within a distant flexible lid region, was recently demonstrated. This cysteine forms a hemithioacetal with the pyridoxal aldehyde and is essential for catalysis. Despite the prevalence of these enzymes in various organisms, no tools were yet available to study the relevance of this lid residue. Here, we introduce pyridoxal probes, each equipped with an electrophilic trapping group in place of the aldehyde to target PLK reactive lid cysteines as a mimic of hemithioacetal formation. The addition of alkyne handles placed at two different positions within the pyridoxal structure facilitates enrichment of PLKs from living cells. Interestingly, depending on the position, the probes displayed a preference for either Gram-positive or Gram-negative PLK enrichment. By applying the cofactor traps, we were able to validate not only previously investigated Staphylococcus aureus and Enterococcus faecalis PLKs but also Escherichia coli and Pseudomonas aeruginosa PLKs, unravelling a crucial role of the lid cysteine for catalysis. Overall, our tailored probes facilitated a reliable readout of lid cysteine containing PLKs, qualifying them as chemical tools for mining further diverse proteomes for this important enzyme class.Microfluidic flow in lab-on-a-chip devices is typically very sensitive to the variable physical properties of complex samples, e.g., biological fluids. Here, evaporation-driven fluid transport (transpiration) is achieved in a configuration that is insensitive to interfacial tension, salinity, and viscosity over a wide range. Micropillar arrays ("pillar cuvettes") were preloaded by wicking a known volatile fluid (water) and then adding a microliter sample of salt, surfactant, sugar, or saliva solution to the loading zone. As the preloaded fluid evaporates, the sample is reliably drawn from a reservoir through the pillar array at a rate defined by the evaporation of the preloaded fluid (typically nL/s). Including a reagent in the preloaded fluid allows photometric reactions to take place at the boundary between the two fluids. In this configuration, a photometric signal enhancement is observed and chemical analysis is independent of both humidity and temperature. The ability to reliably transport and sense an analyte in microliter volumes without concern over salt, surfactant, viscosity (in part), humidity, and temperature is a remarkable advantage for analytical purposes.Metal-organic frameworks (MOFs) can be designed for chemical applications by modulating the size and shape of intracrystalline pores through selection of their nodes and linkers. Zirconium nodes with variable connectivity to organic linkers allow for a broad range of topological nets that have diverse pore structures even for a consistent set of linkers. Identifying an optimal pore structure for a given application, however, is complicated by the large material space of possible MOFs. In this work, molecular dynamics simulations were used to determine how a MOF's topology affects the diffusion of propane and isobutane over the full range of loadings and to understand how MOFs can be tuned to reduce transport limitations for applications in separations and catalysis. High-throughput simulation techniques were employed to efficiently calculate loading-dependent diffusivities in 38 MOFs. The results show that topologies with higher node connectivity have reduced alkane diffusivities compared to topologies with lower node connectivity. link2 Molecular siting techniques were used to elucidate how the pore structures in different topologies affect adsorbate diffusivities.Bladder cancer (BC) is among the most common tumors with a high recurrence rate, necessitating noninvasive and sensitive diagnostic methods. link3 Accurate detection of exfoliated tumor cells (ETCs) in urine is crucial for noninvasive BC diagnosis but suffers from limited sensitivity when ETCs are rare and confounded by reactive, regenerative, or reparative cells. Single-cell sequencing (SCS) enables accurate detection of ETCs by surveying oncogenic driver mutations or genome-wide copy number alternations. To overcome the low-throughput limitation of SCS, we report a SCS-validated cellular marker, hexokinase 2 (HK2), for high-throughput screening cells in urine and detecting ETCs engaging elevated glycolysis. In the SCS-based training set, a total of 385 cells from urine samples of eight urothelial carcinoma (UC) patients were sequenced to establish a HK2 threshold that achieved >90% specificity for ETC detection. This urine-based HK2 assay was tested with a blinded patient group (n = 384) including UC and benign genitourinary disorders as a validation cohort for prospectively evaluating diagnostic accuracy. The sensitivity, specificity, positive predictive value, and negative predictive value of the assay were 90, 88, 83, and 93%, respectively, which were superior to urinary cytology. For investigating the potential to be a screening test, the HK2 assay was tested with a group of healthy individuals (n = 846) and a 6-month follow-up. The specificity was 98.4% in this health group. Three participants were found to have >5 putative ETCs that were sequenced to exhibit recurrent copy number alternations characteristic of malignant cells, demonstrating early BC detection before current clinical methods.Increasing evidence demonstrates that optogenetics contributes to the regulation of brain behavior, cognition, and physiology, particularly during myelination, potentially allowing for the bidirectional modulation of specific cell lines with spatiotemporal accuracy. However, the type of cell to be targeted, namely, glia vs neurons, and the degree to which optogenetically induced cell activity can regulate myelination during the development of the peripheral nervous system (PNS) are still underexplored. Herein, we report the comparison of optogenetic stimulation (OS) of Schwann cells (SCs) and motor neurons (MNs) for activation of myelination in the PNS. Capitalizing on these optogenetic tools, we confirmed that the formation of the myelin sheath was initially promoted more by OS of calcium translocating channelrhodopsin (CatCh)-transfected SCs than by OS of transfected MNs at 7 days in vitro (DIV). Additionally, the level of myelination was substantially enhanced even until 14 DIV. Surprisingly, after OS of SCs, > 91.1% ± 5.9% of cells expressed myelin basic protein, while that of MNs was 67.8% ± 6.1%. The potent effect of OS of SCs was revealed by the increased thickness of the myelin sheath at 14 DIV. Thus, the OS of SCs could highly accelerate myelination, while the OS of MNs only somewhat promoted myelination, indicating a clear direction for the optogenetic application of unique cell types for initiating and promoting myelination. Together, our findings support the importance of precise cell type selection for use in optogenetics, which in turn can be broadly applied to overcome the limitations of optogenetics after injury.Cancer phototheranostics in the second near-infrared window (NIR-II, 1000-1700 nm) has recently attracted much attention owing to its high efficacy and good safety compared with that in the first near-infrared window (NIR-I, 650-950 nm). However, the lack of theranostic nanoagents with active-targeting features limits its further application in cancer precision therapies. Herein, we constructed platelet-camouflaged nanoprobes with active-targeting characteristics for NIR-II cancer phototheranostics. The as-prepared biomimetic nanoprobes can not only escape phagocytosis by macrophages but also specifically bind to CD44 on the surface of most cancer cells. We evaluated the active-targeting performance of biomimetic nanoprobes in pancreatic cancer, breast cancer, and glioma mouse models and achieved NIR-II photoacoustic imaging with a high signal-to-background ratio and photothermal treatment with excellent tumor growth inhibition. Our results show the great potential of platelet-camouflaged nanoprobes with NIR-II active-targeting features for cancer precision diagnosis and efficient therapies.We report the mechanism of hydrogel formation in dilute aqueous solutions (>15 mg/mL) by 2 nm metal-organic cages (MOCs). Experiments and all-atom simulations confirm that with the addition of small electrolytes, the MOCs self-assemble into 2D nanosheets via counterion-mediated attraction because of their unique molecular structure and charge distribution as well as σ-π interactions. The stiff nanosheets are difficult to bend into 3-D hollow, spherical blackberry type structures, as observed in many other macroion systems. Instead, they stay in solution and their very large excluded volumes lead to gelation at low (∼1.5 wt %) MOC concentrations, with additional help from hydrophobic and partial π-π interactions similar to the gelation of graphene oxides.