Discovery of the first selective, small-molecule GFRα2/3 inhibitors through DNA-encoded library technology.

Studies have shown that disrupting the formation of the ligand-RET-GFRα complex could be an effective way of treating pain and itch. Compared to traditional high-throughput screens, DNA encoded libraries (DELs) have distinguished themselves as a powerful technology for hit identification in recent years. The present work demonstrates the use of DEL technology identifying compound 16 as the first GFRa2/GFRa3 small molecule inhibitor (0.1/0.2 µM respectively) selective over RET. This molecule represents an opportunity to advance the development of small-molecule inhibitors targeting the GFRα-RET interface for the treatment of pain and itch.

A Meta-analysis Reveals Global Change Stressors Potentially Aggravate Mercury Toxicity in Marine Biota.

Growing evidence demonstrates that global change can modulate mercury (Hg) toxicity in marine organisms; however, the consensus on such effect is lacking. Here, we conducted a meta-analysis to evaluate the effects of global change stressors on Hg biotoxicity according to the IPCC projections (RCP 8.5) for 2100, including ocean acidification (-0.4 units), warming (+4 °C), and their combination (acidification-warming). The results indicated an overall aggravating effect (ln RRΔ = -0.219) of global change on Hg toxicity in marine organisms, while the effect varied with different stressors; namely, acidification potentially alleviates Hg biotoxicity (ln RRΔ = 0.117) while warming and acidification-warming have an aggravating effect (ln RRΔ = -0.328 and -0.097, respectively). Moreover, warming increases Hg toxicity in different trophic levels, i.e., primary producers (ln RRΔ = -0.198) < herbivores (ln RRΔ = -0.320) < carnivores (ln RRΔ = -0.379), implying increasing trends of Hg biomagnification through the food web. Notably, ocean hypoxia appears to boost Hg biotoxicity, although it was not considered in our meta-analysis because of the small sample size. Given the persistent global change and combined effects of these stressors in marine environments, multigeneration and multistressor research is urgently needed to fully disclose the impacts of global change on Hg pollution and its risk.

Multistress Interplay: Time and Duration of Ocean Acidification Modulate the Toxicity of Mercury and Other Metals.

The current understanding of multistress interplay assumes stresses occur in perfect synchrony, but this assumption is rarely met in the natural marine ecosystem. To understand the interplay between nonperfectly overlapped stresses in the ocean, we manipulated a multigenerational experiment (F0-F3) to explore how different temporal scenarios of ocean acidification will affect mercury toxicity in a marine copepod Pseudodiaptomus annandalei. We found that the scenario of past acidification aggravated mercury toxicity but current and persistent acidification mitigated its toxicity. We specifically performed a proteomics analysis for the copepods of F3. The results indicated that current and persistent acidification initiated the energy compensation for development and mercury efflux, whereas past acidification lacked the barrier of H+ and had dysfunction in the detoxification and efflux system, providing a mechanistic understanding of mercury toxicity under different acidification scenarios. Furthermore, we conducted a meta-analysis on marine animals, demonstrating that different acidification scenarios could alter the toxicity of several other metals, despite evidence from nonsynchronous scenarios remaining limited. Our study thus demonstrates that time and duration of ocean acidification modulate mercury toxicity in marine copepods and suggests that future studies should move beyond the oversimplified scenario of perfect synchrony in understanding multistress interaction.

High-performance pyrite nano-catalyst driven photothermal/chemodynamic synergistic therapy for Osteosarcoma.

Osteosarcoma (OS) is an aggressive bone tumor with strong invasiveness, rapid metastasis, and dreadful mortality. Chemotherapy is a commonly used approach for OS treatment but is limited by the development of drug resistance and long-term adverse effects. To date, OS still lacks the curative treatment. Herein, we fabricated pyrite-based nanoparticles (FeS2@CP NPs) as synergetic therapeutic platform by integrating photothermal therapy (PTT) and chemo-dynamic therapy (CDT) into one system. The synthetic FeS2@CP NPs showed superior Fenton reaction catalytic activity. FeS2@CP NPs-based CDT efficaciously eradicated the tumor cells by initiating dual-effect of killing of apoptosis and ferroptosis. Furthermore, the generated heat from FeS2@CP under near-infrared region II (NIR-II) laser irradiation could not only inhibit tumor's growth, but also promote tumor cell apoptosis and ferroptosis by accelerating •OH production and GSH depletion. Finally, the photothermal/NIR II-enhanced CDT synergistic therapy showed excellent osteosarcoma treatment effects both in vitro and in vivo with negligible side effects. Overall, this work provided a high-performance and multifunctional Fenton catalyst for osteosarcoma synergistic therapy, which provided a pathway for the clinical application of PTT augmented CDT.

Mechanisms of adsorption and functionalization of biochar for pesticides: A review.

Agricultural production relies heavily on pesticides. However, factors like inefficient application, pesticide resistance, and environmental conditions reduce their effective utilization in agriculture. Subsequently, pesticides transfer into the soil, adversely affecting its physicochemical properties, microbial populations, and enzyme activities. Different pesticides interacting can lead to combined toxicity, posing risks to non-target organisms, biodiversity, and organism-environment interactions. Pesticide exposure may cause both acute and chronic effects on human health. Biochar, with its high specific surface area and porosity, offers numerous adsorption sites. Its stability, eco-friendliness, and superior adsorption capabilities render it an excellent choice. As a versatile material, biochar finds use in agriculture, environmental management, industry, energy, and medicine. Added to soil, biochar helps absorb or degrade pesticides in contaminated areas, enhancing soil microbial activity. Current research primarily focuses on biochar produced via direct pyrolysis for pesticide adsorption. Studies on functionalized biochar for this purpose are relatively scarce. This review examines biochar's pesticide absorption properties, its characteristics, formation mechanisms, environmental impact, and delves into adsorption mechanisms, functionalization methods, and their prospects and limitations.

Energy-Efficient and Highly Reliable Geographic Routing Based on Link Detection and Node Collaborative Scheduling in WSN.

Energy efficiency and data reliability are important indicators to measure network performance in wireless sensor networks. In existing research schemes of routing protocols, the impact of node coverage on the network is often ignored, and the possibility that multiple sensor nodes may sense the same spatial point is not taken into account, which results in a waste of network resources, especially in large-scale networks. Apart from that, the blindness of geographic routing in data transmission has been troubling researchers, which means that the nodes are unable to determine the validity of data transmission. In order to solve the above problems, this paper innovatively combines the routing protocol with the coverage control technique and proposes the node collaborative scheduling algorithm, which fully considers the correlation characteristics between sensor nodes to reduce the number of active working nodes and the number of packets generated, to further reduce energy consumption and network delay and improve packet delivery rate. In order to solve the problem of unreliability of geographic routing, a highly reliable link detection and repair scheme is proposed to check the communication link status and repair the invalid link, which can greatly improve the packet delivery rate and throughput of the network, and has good robustness. A large number of experiments demonstrate the effectiveness and superiority of our proposed scheme and algorithm.

Stroke as initial manifestation of non-small cell lung cancer with Trousseau syndrome.

OBJECTIVE: Stroke is a rare but fatal complication of advanced cancer with Trousseau syndrome, especially as initial symptoms. Here, we report the clinical characteristics, treatment, and prognosis of patients with non-small cell lung cancer (NSCLC) who initially presenting with acute multiple cerebral infarction. METHODS: The clinical characteristics, imaging, treatment, and oncological outcomes of 10 patients diagnosed with Trousseau syndrome and NSCLC between 2015 and 2021 at Guangdong Sanjiu Brain Hospital were retrospectively collected and analyzed. The clinical course of two typical cases were presented. RESULTS: All 10 patients with pathologically confirmed lung adenocarcinoma initially presented with neurological symptoms, including hemiplegic paralysis (7 patients, 70%), dizziness (5 patients, 50%), and unclear speech (3 patients, 30%). The median age was 63.5 years. Eight and two cases were stage III and IV, respectively, at the initial diagnosis. Five patients underwent driver gene testing, revealing three patients with EGFR-sensitive mutations, one patient with ALK fusion, and one patient with wild-type EGFR. All 10 patients received antiplatelet therapy, and six patients subsequently received anti-cancer treatment. The median overall survival of the patients was 8.5 months (95% confidence interval) and 1-year survival rate was 57.1%. Patients who received antitumor treatment, especially those harboring driver gene mutations and received tyrosine kinase inhibitors, had better neurological symptom recovery and superior oncological prognosis (median overall survival, not reached versus 7.4 months, p = 0.038). CONCLUSION: Trousseau syndrome, presenting as multiple cerebral infarctions, is a rare complication of lung adenocarcinoma. Both antiplatelet and antitumor treatment are recommended to achieve better neurological recovery and oncological prognosis in these patients.

Discovery and development of benzene sulfonamide derivatives as anti-hepatic fibrosis agents.

A novel benzene sulfonamide compound named IMB16-4 exhibits excellent anti-hepatic fibrosis activity in a recent study. To develop potential anti-hepatic fibrosis agents, a series of benzene sulfonamide derivatives were designed and synthesized based on the scaffold of the lead compound IMB16-4. As it turned out, most of the derivatives displayed potential anti-hepatic fibrosis activity, among which, compounds 11a, 11b, 11d, 13a, 36b, and 47b exhibited inhibition rates of 42.3%, 48.7%, 42.4%, 40.0%, 39.4%, and 49.3%, respectively, which were equivalent to the control IMB16-4 with an inhibition rate of 35.9%, Costunolide with an inhibition rate of 45.4%, and much more potent than that of Epigallocatechin gallate (EGCG) with an inhibition rate of 25.3%. Especially, compounds 46a, 46b, and 46c exhibited excellent anti-hepatic fibrosis activity with inhibition rates of 61.7%, 54.8%, and 60.7%, which were almost 1.5-fold inhibition rates of IMB16-4. In addition, compounds 46a, 46b, and 46c exhibited remarkable inhibitory activity in the gene expression of COL1A1, MMP-2, and the protein expression of COL1A1, FN, α-SMA, and TIMP-1 by inhibiting the JAK1-STAT1/3 pathway. These findings furnished valuable inspiration for the further development of anti-hepatic fibrosis agents.

Molecular basis of USP7 inhibition by selective small-molecule inhibitors.

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.

Defective zirconium/titanium bimetallic metal-organic framework as a highly selective and sensitive electrochemical aptasensor for deoxynivalenol determination in foodstuffs.

An electrochemical aptsensor for deoxynivalenol determination was successfully designed and constructed based on a defective bimetallic organic framework (denoted as ZrTi-MOF). The high porosity, large specific surface area, several structural defects, mixed metal clusters, and rich functionality of ZrTi-MOF markedly enhanced its electrochemical activity and facilitated the aptamer immobilization. As a result, the ZrTi-MOF-based aptasensor shows high sensitivity to detect deoxynivalenol via specific recognition between aptamer and deoxynivalenol, as well as the formation of aptamer-deoxynivalenol complex. On this basis, the developed ZrTi-MOF-based impedimetric aptasensor showed a low detection limit of 0.24 fg mL-1 for deoxynivalenol determination in the deoxynivalenol concentration range 1 fg mL-1- 1 ng mL-1 under optimized conditions, which also exhibited satisfactory selectivity, stability, reproducibility, and regenerability. Furthermore, determination of deoxynivalenol was achieved in bread and wheat flour samples via the developed ZrTi-MOF-based deoxynivalenol aptasensor. The result from this study showed that the ZrTi-MOF-based electrochemical aptasensor could become a promising strategy for detecting deoxynivalenol in foodstuffs in the future.

Triazine-based covalent-organic framework embedded with cuprous oxide as the bioplatform for photoelectrochemical aptasensing Escherichia coli.

A superior photoelectrochemical (PEC) aptasensor was manufactured for the detection of Escherichia coli (E. coli) based on a hybrid of triazine-based covalent-organic framework (COF) and cuprous oxide (Cu2O). The COF synthesized using 1,3,5-tris(4-aminophenyl)-benzene (TAPB) and 1,3,5-triformylphloroglucinol (Tp) as building blocks acted as a scaffold for encapsulated Cu2O nanoparticles (denoted as Cu2O@TAPB-Tp-COF), which then was employed as the bioplatform for anchoring E. coli-targeted aptamer. Cu2O@Cu@TAPB-Tp-COF demonstrated enhanced separation of the photogenerated carriers and photoabsorption ability and boosted photoelectric conversion efficiency. The developed Cu2O@TAPB-Tp-COF-based PEC aptasensor exhibited a lower detection limit of 2.5 CFU mL-1 toward E. coli within a wider range of 10 CFU mL-1 to 1 × 104 CFU mL-1 than most of reported aptasensors for determining foodborne bacteria, together with high selectivity, good stability, and superior ability and reproducibility. The recoveries of E. coli spiked into milk and bread samples ranged within 95.3-103.6% and 96.6-102.8%, accompanying with low RSDs of 1.37-4.48% and 1.74-3.66%, respectively. The present study shows a promising alternative for the sensitive detection of foodborne bacteria from complex foodstuffs and pathogenic bacteria-polluted environment.

Sensitive detection of Escherichia coli in diverse foodstuffs by electrochemical aptasensor based on 2D porphyrin-based COF.

The two-dimensional porphyrin-based covalent organic framework (denoted by Tph-TDC-COF) was used as the sensitive layerto build an aptamer-based electrochemical sensor for the detection of Escherichia coli (E.coli). Tph-TDC-COF produced with 5,10,15,20-tetrakis(4-aminophenyl)-21H, 23H-porphine (Tph) and [2,2'-bithiophene]-2,5'-dicarbaldehyde (TDC) as building blocks exhibited a highly conjugated structure, outstanding conductivity, large specific surface area, and strong bioaffinity towards aptamers. The adoption of Tph-TDC-COF-modified electrode resulted in improved sensing performance and increased anchoring affinity toward the E.coli-targeted aptamer. Under optimal conditions, the Tph-TDC-COF-based electrochemical aptasensor demonstrated an extremely low detection limit of 0.17 CFU mL-1 for E.coli detection within a linear range of 10 to 1 × 108 CFU mL-1, accompanied by good stability, excellent reproducibility and regeneration ability, and wide practical applications. The current electrochemical aptasensing technique has the potential to be extended to detect different foodborne bacteria using specific aptamer, therefore widening the application of COFs in biosensing and food safety fields.

New Approach to Generate Ratiometric Signals on Immunochromatographic Strips for Small Molecules.

The self-calibration capability of ratiometric signals has been widely considered to enhance the accuracy, sensitivity, and anti-interference ability of immunoassays. Exploring a new approach to generate ratiometric signals can provide more options for various requirements. Herein, we integrated the negative-readout competitive and positive-readout noncompetitive immunoassays into a single assay by employing different color tracers, labeled peptidomimetic and anti-immunocomplex peptides, to create a new unconstrained ratiometric signal approach. Using an immunochromatographic strip (ICS) and a fungicide benzothiostrobin as the analytical platform and analyte, respectively, we showed that this approach can be extensively applied to fluorescence and colorimetry readouts, which have also been proven for strong anti-interference ability to an external light environment. Moreover, the enormous intuitional color changes of ratiometric fluorescent and colorimetric ICSs (RFICS and RCICS) enabled the formation of the color reference cards (like the pH paper) for visual judgment. After adaptation with a portable smartphone, the quantitative detection limits for RFICS and RCICS were 0.17 and 0.44 ng mL-1, respectively. In addition, the ICSs showed good accuracy for the detection of benzothiostrobin in spiked samples.

Transmission barrier of the blaKPC plasmid mediated by type I restriction-modification systems in Escherichia coli.

BACKGROUND: Transportation of carbapenem-resistant plasmids contributes to carbapenem resistance in Gram-negative bacteria. KPC enzymes are the most clinically important enzymes among carbapenem-resistant Klebsiella pneumoniae, whereas the rate of blaKPC in Escherichia coli is low. The CRISPR-Cas system and restriction-modification system (R-M system) in bacteria defend against invading genomes. Currently, the role of the immune systems in the low rate of KPC-producing E. coli remains unclear. OBJECTIVES: We investigated the relationship between immune systems and the low detection rate of blaKPC in E. coli. METHODS: We searched for blaKPC among 1039 E. coli whole genomes available in GenBank using nucleotide BLAST. CRISPR-Cas systems and the R-M system were detected in all strains having the ST as blaKPC-positive strains. Nucleotide BLAST was used to search for protospacers on blaKPC plasmids. A conjugation assay was performed to determine whether the R-M system influences the acquisition of blaKPC plasmids by E. coli. RESULTS: ST131 was the dominant ST of KPC-producing E. coli and IncN was the main plasmid type (12/32). CRISPR-Cas systems were frequently present in E. coli carrying blaKPC. Furthermore, CRISPR-Cas systems in E. coli didn't target plasmids with blaKPC. Type I R-M systems were rare in KPC-producing E. coli, but significantly over-represented in KPC-negative strains. E. coli DH5α with hsdR deletion accepted blaKPC-carrying plasmids, whereas those with hsdR complementation impeded blaKPC-carrying plasmid conjugation. CONCLUSIONS: Horizontal transmission of blaKPC occurs among E. coli. The type I R-M system is associated with the defence against blaKPC plasmid transport into E. coli.

Synthesis and biological evaluation of novel N, N'-diarylurea derivatives as potent antibacterial agents against MRSA.

A series of new N, N'-diarylurea derivatives were designed and synthesized, some of which exhibited potent antibacterial activity against the drug-susceptible and drug-resistant Gram-positive strains. Especially, compounds 2c, 2g-2l showed broader antibacterial spectrum and more potent antibacterial activity (MIC = 0.30-2.72 µM) against MRSA and MRSE than the control levofloxacin (MIC = 0.69-22.14 µM). In addition, compounds 2c, 2g, 2h and 2l exhibited much better antibacterial activity (MIC = 1.29-2.86 µM) against VRE (E. faecium) than sorafenib (MIC = 275.37 µM), PK150 (MIC = 5.07-10.13 µM) and SC78 (MIC = 2.40-4.79 µM). More importantly, the low cytotoxicity of compounds on cell lines HeLa and HepG2 implied a relatively wide therapeutic window, which was of high importance for further study.

Design, synthesis, and anti-influenza A virus activity evaluation of novel indole containing derivatives of triazole.

We designed and synthesized 18 substituted indole derivatives containing a triazole scaffold as novel anti-influenza A virus candidates using a bio-isosteric and scaffold-hopping strategy from the lead compound 4-32-2. Most of the target compounds (eg: 6, 7a, 7d, 7f-j, 7l, 7m, 7o, 7q) exhibited potent anti-influenza A virus activity and low cytotoxicity in vitro. In particular, 7a exhibited the most potent anti-IAV activity (IC50: 1.34 ± 0.13 µM) with low cytotoxicity (CC50: > 100 µM), and high selectivity index (SI: > 74.63), which provides a new chemical scaffold for the development of novel anti-IAV drug.

Diel Fluctuation Superimposed on Steady High pCO2 Generates the Most Serious Cadmium Toxicity to Marine Copepods.

Coastal systems experience diel fluctuation of pCO2 and cadmium (Cd) pollution; nevertheless, the effect of fluctuating pCO2 on Cd biotoxicity is poorly known. In this study, we initially performed the isotopically enriched organism bioassay to label Tigriopus japonicus with 113Cd (5 µg/L) to determine the Cd accumulation rate constant (kaccu) under ambient (400 µatm) and steadily (1000 µatm) and fluctuatingly elevated (1000 ± 600 µatm) pCO2 conditions for 48 h. Next, T. japonicus was interactively subjected to the above pCO2 exposures at Cd (control, 5, and 500 µg/L) treatments for 7 d. Biochemical and physiological responses for copepods were analyzed. The results showed that steadily increased pCO2 facilitated Cd bioaccumulation compared to ambient pCO2, and it was more under fluctuating acidification conditions. Despite compensatory reactions (e.g., increased energy production), Cd ultimately induced oxidative damage and apoptosis. Meanwhile, combined treatment exhibited higher toxicity (e.g., increased apoptosis) relative to Cd exposure, and even more if fluctuating acidification was considered. Intriguingly, fluctuating acidification inhibited Cd exclusion in Cd-treated copepods compared to steady acidification, linking to higher Cd kaccu and bioaccumulation. Collectively, CO2-driven acidification could aggravate Cd toxicity, providing a mechanistic understanding of the interaction between seawater acidification and Cd pollution in marine copepods.

Metabolic Adaptation of a Globally Important Diatom following 700 Generations of Selection under a Warmer Temperature.

Diatoms, accounting for 40% of the marine primary production and 20% of global carbon dioxide fixation, are threatened by the ongoing ocean warming (OW). However, whether and how these ecologically important phytoplankton adapt to OW remains poorly unknown. Here, we experimentally examined the metabolic adaptation of a globally important diatom species Skeletonema dohrnii (S. dohrnii) to OW at two elevated temperatures (24 and 28 °C compared with 20 °C) under short-term (∼300 generations) and long-term (∼700 generations) selection. Both warming levels significantly increased the cell growth rate but decreased the chlorophyll a content. The contents of particulate organic carbon (POC) and particulate organic nitrogen (PON) decreased significantly initially (i.e., until 300 generations) at two temperature treatments but completely recovered after 700 generations of selection, suggesting that S. dohrnii ultimately developed thermal adaptation. Proteomic analysis demonstrated that elevated temperatures upregulated energy metabolism via glycolysis, tricarboxylic acid cycle, and fatty acid oxidation as well as nitrogen acquisition and utilization, which in turn reduced substance storage because of trade-off in the 300th generation, thus decreasing POC and PON. Interestingly, populations at both elevated temperatures exhibited significant proteome plasticity in the 700th generation, as primarily demonstrated by the increased lipid catabolism and glucose accumulation, accounting for the recovery of POC and PON. Changes occurring in cells at the 300th and 700th generations demonstrate that S. dohrnii can adapt to the projected OW, and readjusting the energy metabolism is an important adaptive strategy.

A kind of HIV-1 protease inhibitors containing phenols with antiviral activity against DRV-resistant variants.

Based upon the preliminary design of enhancing genetic barrier to drug-resistant viral mutants by maximizing hydrogen-bonding or other van der Waals contacts, we have designed, synthesized and biologically evaluated a new class of HIV-1 protease inhibitors with phenol derived P2 ligands and nitro or halogens in P2' ligands. Results indicate that a majority of inhibitors exhibit robust enzyme inhibitory with IC50 values in picomolar or single digit nanomolar ranges. Among which, compound 17d displays potency with IC50 value of 21 pM and high protease selectivity. Of note, 17d exhibits greater antiviral activity against the DRV-resistant variant than the efficacy against the wild type virus. Furthermore, the molecular modeling studies demonstrate important interactions between 17d and the active sites of both the wild-type and DRV-resistant HIV-1 protease, as well as furnish insights for further optimization of new inhibitors.

Biotin-labelled peptidomimetic for competitive time-resolved fluoroimmunoassay of benzothiostrobin.

In recent years, more and more functional peptide ligands have been identified from phage display libraries and served the immunoassay of small molecules. After the identification, the phage particle instead limits further application of peptide ligands, so it is of great significance to explore the peptide ligand as an independent detection reagent. In this work, the identified peptidomimetic of benzothiostrobin was synthesized and labelled with biotin, which was combined with Eu3+-labelled streptavidin to develop the peptide-based time-resolved fluoroimmunoassay (P-TRFIA). Under the optimal conditions, the half-maximum inhibitory concentration (IC50) of proposed P-TRFIA is 3.63 ng mL-1, which is similar to the TRFIA using phage-borne peptidomimetic and Eu3+-labelled anti-phage antibody (IC50: 4.55 ng mL-1), also more sensitive than previously reported immunoassays for benzothiostrobin. In addition, the proposed P-TRFIA shows excellent specificity and accuracy for analysis of spiked samples, and its detection results shows good consistency with high-performance liquid chromatography for the detection of environment and agro-products samples with unknown benzothiostrobin concentrations.