Targeting RNA G-quadruplex with repurposed drugs blocks SARS-CoV-2 entry.

The rapid emergence of SARS-CoV-2 variants of concern, the complexity of infection, and the functional redundancy of host factors, underscore an urgent need for broad-spectrum antivirals against the continuous COVID-19 pandemic, with drug repurposing as a viable therapeutic strategy. Here we report the potential of RNA G-quadruplex (RG4)-targeting therapeutic strategy for SARS-CoV-2 entry. Combining bioinformatics, biochemical and biophysical approaches, we characterize the existence of RG4s in several SARS-CoV-2 host factors. In silico screening followed by experimental validation identify Topotecan (TPT) and Berbamine (BBM), two clinical approved drugs, as RG4-stabilizing agents with repurposing potential for COVID-19. Both TPT and BBM can reduce the protein level of RG4-containing host factors, including ACE2, AXL, FURIN, and TMPRSS2. Intriguingly, TPT and BBM block SARS-CoV-2 pseudovirus entry into target cells in vitro and murine tissues in vivo. These findings emphasize the significance of RG4 in SARS-CoV-2 pathogenesis and provide a potential broad-spectrum antiviral strategy for COVID-19 prevention and treatment.

Programmable DNA Scaffolds Enable Orthogonal Engineering of Cell Membrane-Based Nanovesicles for Therapeutic Development.

Cell membrane-based nanovesicles (CMNVs) play pivotal roles in biomolecular transportation in living organisms and appear as attractive bioinformed nanomaterials for theranostic applications. However, the current surface-engineering technologies are limited in flexibility and orthogonality, making it challenging to simultaneously display multiple different ligands on the CMNV surface in a precisely controlled manner. Here, we developed a DNA scaffold-programmed approach to orthogonally engineer CMNVs with versatile ligands. The designed DNA scaffolds can rapidly anchor onto the CMNV surface, and their unique sequences and hybridized properties enable independent control of the loading of multiple different types of biomolecules on the CMNVs. As a result, the orthogonal engineering of CMNVs with a renal targeted peptide and a therapeutic protein at controlled ratios demonstrated an enhanced renal targeting and repair potential in vivo. This study highlights that a DNA scaffold-programmed platform can provide a potent means for orthogonal and flexible surface engineering of CMNVs for diverse therapeutic purposes.

Host-microbiota interactions contributing to the heterogeneous tumor microenvironment in colorectal cancer.

Colorectal cancer (CRC) exhibits pronounced heterogeneity and is categorized into four widely accepted consensus molecular subtypes (CMSs) with unique tumor microenvironments (TMEs). However, the intricate landscape of the microbiota and host-microbiota interactions within these TMEs remains elusive. Using RNA-sequencing data from The Cancer Genome Atlas, we analyzed the host transcriptomes and intratumoral microbiome profiles of CRC samples. Distinct host genes and microbial genera were identified among the CMSs. Immune microenvironments were evaluated using CIBERSORTx and ESTIMATE, and microbial coabundance patterns were assessed with FastSpar. Through LASSO penalized regression, we explored host-microbiota associations for each CMS. Our analysis revealed distinct host gene signatures within the CMSs, which encompassed ferroptosis-related genes and specific immune microenvironments. Moreover, we identified 293, 153, 66, and 109 intratumoral microbial genera with differential abundance, and host-microbiota associations contributed to distinct TMEs, characterized by 829, 1,270, 634, and 1,882 robust gene-microbe associations for each CMS in CMS1-CMS4, respectively. CMS1 featured inflammation-related HSF1 activation and gene interactions within the endothelin pathway and Flammeovirga. Integrin-related genes displayed positive correlations with Sutterella in CMS2, whereas CMS3 spotlighted microbial associations with biosynthetic and metabolic pathways. In CMS4, genes involved in collagen biosynthesis showed positive associations with Sutterella, contributing to disruptions in homeostasis. Notably, immune-rich subtypes exhibited pronounced ferroptosis dysregulation, potentially linked to tissue microbial colonization. This comprehensive investigation delineates the diverse landscapes of the TME within each CMS, incorporating host genes, intratumoral microbiota, and their complex interactions. These findings shed light on previously uncharted mechanisms underpinning CRC heterogeneity and suggest potential therapeutic targets.NEW & NOTEWORTHY This study determined the following: 1) providing a comprehensive landscape of consensus molecular subtype (CMS)-specific tumor microenvironments (TMEs); 2) constructing CMS-specific networks, including host genes, intratumoral microbiota, and enriched pathways, analyzing their associations to uncover unique patterns that demonstrate the intricate interplay within the TME; and 3) revealing a connection between immune-rich subtypes and ferroptosis activation, suggesting a potential regulatory role of the microbiota in ferroptosis dysregulation of the colorectal cancer TME.

Multifunctional DNA-Based Hydrogel Promotes Diabetic Alveolar Bone Defect Reconstruction.

Diabetic alveolar bone defect (DABD) causes persistent bacterial infection, prolonged inflammation, and delayed bone healing, making it a considerable clinical challenge. In this study, by integrating silver nanoclusters (AgNCs) and M2 macrophage-derived extracellular vesicles (M2EVs), a multifunctional DNA-based hydrogel, called Agevgel, is developed with antibacterial, anti-inflammatory, immunomodulatory, and osteogenic properties to promote DABD rebuilding. AgNCs are tightly embedded into the DNA scaffolds and exhibit effective anti-bacterial activity, while immunomodulatory M2EVs are encapsulated within the shape-variable DNA scaffolds and exhibit potent anti-inflammatory and osteogenic properties. The results reveal that Agevgel effectively prolongs the local retention time and bioactivity of M2EVs in vivo. In particular, the sustained release of M2EVs can last for at least 7 days when applying Agevgel to DABD. Compared to free M2EVs or Aggel (AgNCs encapsulated within the DNA hydrogel) treatments, the Agevgel treatment accelerates the defect healing rate of alveolar bone and dramatically improves the trabecular architecture. Mechanistically, Agevgel plays a key role in regulating macrophage polarization and promoting the expression of proliferative and osteogenic factors. In summary, Agevgel provides a comprehensive treatment strategy for DABD with a great clinical translational value, highlighting the application of DNA hydrogels as an ideal bioscaffolds for periodontal diseases.

Delivery of nanosecond laser pulses by multi-mode anti-resonant hollow core fiber at 1†µm wavelength.

In this paper we explore the application of low-loss multimode anti-resonant hollow-core fiber (MM-AR-HCF) in the delivery of nanosecond laser pulses at 1 µm wavelength. MM-AR-HCF with large core offers a rich content of low-loss higher-order modes which plays a key role in the efficient coupling and transmission of high-power laser of low beam quality. In the experiment, laser pulses of an average pulse energy of 21.8 mJ with 14.6 ns pulse width (corresponding a peak power of 1.49 MW) are transmitted through MM-AR-HCF of 9.8 m length without damage. 85% transmission efficiency is achieved where the incident laser beam suffers a low beam quality with M2 x and M2 y of 2.18 and 1.99 respectively. Laser-induced damage threshold (LIDT) of MM-AR-HCF was measured to be 22.6 mJ for 85% transmission efficiency, which is 7 times higher than that for a multimode silica optical fiber with a large core of 200 µm.

NAFLDkb: A Knowledge Base and Platform for Drug Development against Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with a broad spectrum of histologic manifestations. The rapidly growing prevalence and the complex pathologic mechanisms of NAFLD pose great challenges for treatment development. Despite tremendous efforts devoted to drug development, there are no FDA-approved medicines yet. Here, we present NAFLDkb, a specialized knowledge base and platform for computer-aided drug design against NAFLD. With multiperspective information curated from diverse source materials and public databases, NAFLDkb presents the associations of drug-related entities as individual knowledge graphs. Practical drug discovery tools that facilitate the utilization and expansion of NAFLDkb have also been implemented in the web interface, including chemical structure search, drug-likeness screening, knowledge-based repositioning, and research article annotation. Moreover, case studies of a knowledge graph repositioning model and a generative neural network model are presented herein, where three repositioning drug candidates and 137 novel lead-like compounds were newly established as NAFLD pharmacotherapy options reusing data records and machine learning tools in NAFLDkb, suggesting its clinical reliability and great potential in identifying novel drug-disease associations of NAFLD and generating new insights to accelerate NAFLD drug development. NAFLDkb is freely accessible at https://www.biosino.org/nafldkb and will be updated periodically with the latest findings.

Copper-doped Lanthanide Coordination Polymers as Luminescent Nanoenzyme for Ratiometric Sensing of H2O2 and Glutathione.

Design and fabrication of integrated multifunctional probes with intrinsic catalytic and detection abilities is of great importance to simplify the operation in biosensing application with high sensitivity. Herein, dual-emitting lanthanide coordination polymers (Ln-CPs) were facilely prepared by self-assembly of guanine diphosphate (GDP), terephthalic acid (TA), Tb3+ and Cu2+ designated as Tb/Cu-GDP/TA CPs. The doped Cu2+ endowed CPs with obviously enhanced peroxidase mimicking activity compared with free Cu2+. In the presence of H2O2, the probe catalyzed the oxidation of TA generating a new blue fluorescent product, while the fluorescence of Tb3+ decreased simultaneously. Therefore, a new sensitive ratiometric fluorescent sensor for H2O2 has been developed with a good linear range from 0.01 to 300 µM and limit of 1.62 nM. Moreover, the proposed platform could be extended to GSH ratiometric assay in the presence of H2O2, and interestingly, the detection performance could be easily adjusted by adding different concentration of H2O2. This work will facilitate the development of luminescent nanoenzymes based on Ln-CPs to construct the simple ratiomatric sensing platform.

Converting Commercial Zn Foils into Single (002)-Textured Zn with Millimeter-Sized Grains for Highly Reversible Aqueous Zinc Batteries.

Rechargeable aqueous zinc batteries are promising but hindered by unfavorable dendrite growth and side reactions on zinc anodes. In this study, we demonstrate a fast melting-solidification approach for effectively converting commercial Zn foils into single (002)-textured Zn featuring millimeter-sized grains. The melting process eliminates initial texture, residual stress, and grain size variations in diverse commercial Zn foils, guaranteeing the uniformity of commercial Zn foils into single (002)-textured Zn. The single (002)-texture ensures large-scale epitaxial and dense Zn deposition, while the reduction in grain boundaries significantly minimizes intergranular reactions. These features enable large grain single (002)-textured Zn shows planar and dense Zn deposition under harsh conditions (100 mA cm-2, 100 mAh cm-2), impressive reversibility in Zn||Zn symmetric cell (3280 h under 1 mA cm-2, 830 h under 10 mAh cm-2), and long cycling stability over 180 h with a high depth of discharge value of 75 %. This study successfully addresses the issue of uncontrollable texture formation in Zn foils following routine annealing treatments with temperatures below the Zn melting point. The findings of this study establish a highly efficient strategy for fabricating highly reversible single (002)-textured Zn anodes.

Protein Phosphatase 5-Recruiting Chimeras for Accelerating Apoptosis-Signal-Regulated Kinase 1 Dephosphorylation with Antiproliferative Activity.

A normal phosphorylation state is essential for the function of proteins. Biased regulation frequently results in morbidity, especially for the hyperphosphorylation of oncoproteins. The hyperphosphorylation of ASK1 at Thr838 leads to a persistently high activity state, which accelerates the course of gastric cancer. Under normal conditions, PP5 specifically dephosphorylates p-ASK1T838 in cells, thereby weakening ASK1 to a low-basal activity state. However, in tumor types, PP5 shows low activity with a self-inhibition mechanism, making p-ASK1T838 remain at a high level. Thus, we aim to design phosphatase recruitment chimeras (PHORCs) through a proximity-mediated effect for specifically accelerating the dephosphorylation of p-ASK1T838. Herein, we describe DDO3711 as the first PP5-recruiting PHORC, which is formed by connecting a small molecular ASK1 inhibitor to a PP5 activator through a chemical linker, to effectively decrease the level of p-ASK1T838 in vitro and in vivo. DDO3711 shows preferable antiproliferative activity (IC50 = 0.5 µM) against MKN45 cells through a direct binding and proximity-mediated mechanism, while the ASK1 inhibitor and the PP5 activator, used alone or in combination, exhibit no effect on MKN45 cells. Using DDO3711, PHORCs are identified as effective tools to accelerate the dephosphorylation of POIs and provide important evidence to achieve precise phosphorylation regulation, which will promote confidence in the further regulation of abnormally phosphorylated oncoproteins.

The impact of climate change and human activities to vegetation carbon sequestration variation in Sichuan and Chongqing.

Exploring the vegetation carbon cycle and the factors influencing vegetation carbon sequestration in areas with complex plateau-basin topography and fragile ecosystems is crucial. In this study, spatial and temporal characteristics of carbon sequestration by vegetation in Sichuan and Chongqing from 2010 to 2020 and the influencing factors were investigated through simulations of net primary productivity (NPP) using the modified Carnegie-Ames-Stanford approach (CASA) and the Thornthwaite Memorial (TM) model and using chemical equations of photochemical reactions. The results indicated that: The spatial distribution of carbon sequestration capacity (CSC) trends showed an increase in the east (the most prominent increased trend along the mountainous areas of the basin) and a decrease in the west (western Sichuan plateau). Differences exist in the impact factors of CSC in different regions. In the basin margins and mountainous areas, where the proportion of forests was high, a combination of climate change and human activities contributed to the increase in CSC. The relatively warm and humid meteorological conditions in the hinterland of the basin were more conducive to the increase in CSC, and climate change also affected the region more significantly. In contrast, in the relatively high altitude of western Sichuan, controlled human activities were the key to improving CSC. The results of the study contribute to the understanding of the basic theory of vegetation carbon cycle in areas with complex plateau-basin topography and fragile ecosystems, as well as to provide suggestions for ecological shelter construction and ecological restoration in the upper Yangtze River.

A microRNA checkpoint for Ca2+ signaling and overload in acute pancreatitis.

Acute pancreatitis (AP) is a common digestive disease without specific treatment, and its pathogenesis features multiple deleterious amplification loops dependent on translation, triggered by cytosolic Ca2+ ([Ca2+]i) overload; however, the underlying mechanisms in Ca2+ overload of AP remains incompletely understood. Here we show that microRNA-26a (miR-26a) inhibits pancreatic acinar cell (PAC) store-operated Ca2+ entry (SOCE) channel expression, Ca2+ overload, and AP. We find that major SOCE channels are post-transcriptionally induced in PACs during AP, whereas miR-26a expression is reduced in experimental and human AP and correlated with AP severity. Mechanistically, miR-26a simultaneously targets Trpc3 and Trpc6 SOCE channels and attenuates physiological oscillations and pathological elevations of [Ca2+]i in PACs. MiR-26a deficiency increases SOCE channel expression and [Ca2+]i overload, and significantly exacerbates AP. Conversely, global or PAC-specific overexpression of miR-26a in mice ameliorates pancreatic edema, neutrophil infiltration, acinar necrosis, and systemic inflammation, accompanied with remarkable improvements on pathological determinants related with [Ca2+]i overload. Moreover, pancreatic or systemic administration of an miR-26a mimic to mice significantly alleviates experimental AP. These findings reveal a previously unknown mechanism underlying AP pathogenesis, establish a critical role for miR-26a in Ca2+ signaling in the exocrine pancreas, and identify a potential target for the treatment of AP.

Association between previous cataract surgery and cognition among middle-aged and older Chinese: the China health and retirement longitudinal study (CHARLS).

BACKGROUND: Cataract is the primary cause of blindness globally, and surgery offers the only method by which to remove cataracts. We aimed to examine whether previous cataract surgery is associated with cognitive function. METHODS: Our study included 13,824 participants. Data from the baseline of the China Health and Retirement Longitudinal Study (CHARLS) were used. The participants were categorized into two groups: with and without previous cataract surgery. Weighted multiple linear regression was used to obtain the ß and 95% confidence intervals (CI). RESULTS: The participants who had previous cataract surgery (n = 261) scored lower in cognition, including both memory and mental state, than those without previous cataract surgery. After adjusting for socioeconomic factors and metabolic measures, a negative association was evident between previous cataract surgery and cognition (ß = -0.647, 95% CI: -1.244, - 0.049). Furthermore, the participants who were older and female demonstrated a decline in cognition, while living in cities and having higher levels education were associated with higher cognition. CONCLUSIONS: Better cognitive function was associated with less previous cataract surgery or cataract occurrence. This suggests that a period of vision loss due to cataract leads to cognitive decline, however further studies are need to dissect the impact of vision loss and cataract surgery on cognitive decline.

Discrimination of Cell Death Types with an Activatable Fluorescent Probe through Visualizing the Lysosome Morphology.

Cell death plays a vital role in body development, maintenance of tissue function, and homeostasis. Accurate evaluation of cell death types is of great importance for pharmacological and pathological research. However, there is a lack of efficient fluorescent probes to discriminate various cell states. Here, we design and synthesize a novel activatable fluorescent probe PNE-Lyso to detect intracellular pH and hexosaminidases with two kinds of fluorescence signals. PNE-Lyso could distinguish dead cells from healthy cells based on a dual-color mode by targeting the lysosome and evaluating lysosomal hexosaminidase activity. Significantly, PNE-Lyso could also discriminate apoptotic and necrotic cells through visualizing lysosome morphology that is adjusted by the integrity of the lysosome membrane. Moreover, probe PNE-Lyso was successfully applied to investigate the drug-induced cell death process. To the best of our knowledge, this work is the first time cell death types have been distinguished based on a single fluorescent probe.

Laser-induced damage of an anti-resonant hollow-core fiber for high-power laser delivery at 1 µm.

We demonstrate high-power laser delivery exceeding 1 kilowatt through a 5-meter homemade anti-resonant hollow-core fiber (AR-HCF) at 1-µm wavelength. Laser-induced damage to the fiber coating and jacket glass is experimentally observed respectively for different incident laser powers from a few hundred watts up to nearly 1.5 kilowatts. The cladding microstructure of the AR-HCF is free of damage at the incident end when 80% of the 1.5-kW incident power is coupled in. The deviation of an incident laser beam from the core to the cladding causes no damage but only deterioration of the coupling efficiency. The potential of the AR-HCF for higher-power laser delivery is discussed.

MicroRNA-146a promotes proliferation, migration, and invasion of HepG2 via regulating FLAP.

Abnormal expression of 5-Lipoxygenase Activating Protein (FLAP) has been detected in many tumor cells. MicroRNAs (miRNAs) negatively regulate gene expression post-transcriptionally by binding to the 3'-untranslated region (3'-UTR) of the target mRNA sequences and have been shown to be involved in various types of cancers. Herein, we aimed to demonstrate the expression of miR-146a and FLAP in human HCC tissues and liver cancer cell lines. We demonstrated that miR-146a expression is overexpressed, while FLAP protein and mRNA are suppressed in hepatocellular carcinoma tissues and HepG2 cells compared to para-carcinoma tissues and HL-7702 cells. Dual luciferase reporter gene assay showed that miR-146a-5p can directly target FLAP mRNA. Knockdown of miR-146a also resulted in increased FLAP expression of cancer cells. Additionally, miR-146a silencing or restoration of FLAP led to a reduction of HepG2 cell proliferation, cell cycle progression, migration, and invasion. This study showed that miR-146a has a stimulatory role in HepG2 cells and promotes HepG2 cell migration and invasion by targeting FLAP mRNA. Thus, miR-146a may be a tumor promoter and a potential therapeutic target for the treatment of HCC patients.

Detecting the combined toxicity of 18 binary and 24 ternary pesticide combinations to carboxylesterase based on fluorescence probe technology.

A rapid test method for the determination of pesticide toxicity was established by using carboxylesterase (CES) and fluorescence probe ACE-NH based on the principle of enzyme inhibition, and this method was applied to detect the combined toxicity of 18 binary and 24 ternary pesticide combinations commonly used for fruits and vegetables to CES. The results show that chlorpyrifos + carbendazim, carbofuran + carbendazim, imidacloprid + carbendazim, imidacloprid + dimethomorph, dimethoate + dimethomorph, prochloraz + carbendazim and imidacloprid + acetamiprid + carbendazim had synergistic effects under three concentration gradients, it indicated that most binary combinations containing carbendazim or imidacloprid had synergistic effects. Based on structure-activity relationship between pesticides and CES, pesticides with phosphate ester bonds had great toxicity to CES, or though they have no toxicity to CES alone, they showed a strong synergistic effect when mixed with other pesticides. Pesticides with amide or ester bond had medium toxicity and little synergistic effect. Pesticides with urea, carbamate or nitrite nitrogen group had little or no toxicity, while there was a strong synergistic effect after mixing with other pesticides. The test method and results in this study can provide scientific basis for risk assessment of cumulative exposure to mixed pesticide residues.

Delivery of CW laser power up to 300 watts at 1080†nm by an uncooled low-loss anti-resonant hollow-core fiber.

In this paper, we report the use of a 3-meter low-loss anti-resonant hollow-core fiber (AR-HCF) to deliver up to 300 W continuous-wave laser power at 1080 nm wavelength from a commercial fiber laser source. A near-diffraction-limited beam is measured at the output of the AR-HCF and no damage to the uncooled AR-HCF is observed for several hours of laser delivery operation. The limit of AR-HCF coupling efficiency and laser-induced thermal effects that were observed in our experiment are also discussed.

Purification, secondary structure and antioxidant activity of metallothionein zinc-binding proteins from Arca subcrenata.

Zinc-binding proteins named MT-M-I and MT-M-II were obtained after purification from metal-exposed hairy clams (Arca subcrenata) using gel permeation and ion-exchange chromatography. MT-M-I and MT-M-II were resolved by ion-exchange chromatography, and they were found to have similar molecular weights. MT-M-I and MT-M-II can bind 6 and 7 equivalents of Zn2+ in vitro, and they showed unusual migration behaviors in Tricine sodium dodecyl sulfate polyacrylamide gel electrophoresis (Tricine-SDS-PAGE). Such migration behaviors may be due to themetal thiolate clusters in these proteins. In terms of amino acid composition, the proportion of cysteine in MT-M-I and MT-M-II was approximately 30%, and glycine accounted for approximately 15%, where as aromatic amino acids were absent. Considering the performance in Tricine-SDS-PAGE and the amino acid compositions, MT-M-I and MT-M-II conform to the molecular characteristics of the metallothionein proteins. The structures were explored using circular dichroism (CD) and Fourier-transform infrared spectroscopy (FTIR). Also determined the antioxidant activities in terms of DPPH radical scavenging ability, hydroxyl radical (·OH) scavenging ability, and ferric-reducing/antioxidant power. The antioxidant activities of MT-M-I were found to be stronger than those of MT-M-II.

Highly Selective Fluorescent Probe Based on Hydroxylation of Phenylboronic Acid Pinacol Ester for Detection of Tyrosinase in Cells.

The detection of tyrosinase, a biomarker for melanoma, is of great significance. Herein, a fluorescent tyrosinase probe, with resorufin as the fluorophore and m-tolylboronic acid pinacol ester as the receptor, is proposed. The response relies on the tyrosinase-catalyzed hydroxylation of phenylboronic acid pinacol ester at an adjacent position followed by 1,6-rearrangement elimination to release resorufin. This probe well quantifies tyrosinase in the range from 1 to 100 U mL-1 with a detection limit of 0.5 U mL-1. Importantly, the probe exhibits high selectivity for tyrosinase over other biological substances including reactive oxygen species. In addition, it is successfully applied to the imaging of tyrosinase in cells. This probe provides a novel platform for selective detection of tyrosinase in biosystems.

Synthesis and application of ratio fluorescence probe for chloride.

As chloride ions (Cl-) play a vital role in maintaining normal physiological activity, detection of chloride ions is quite urgent. Hence, we developed chloride fluorescence probes to highly selectively and sensitively monitor chloride ions. The probe M2 with single emission has a high fluorescence quantum yield (Φ = 45%), and it is capable of quantitative detection of Cl- under physiological conditions (pH = 7.4) and pH = 5.0 with a linear range of 0.1-4.0 mM; nevertheless, it is of the switch-off type. We further synthesized a ratiometric fluorescent probe MY with M2 as raw material, which featured excellent selectivity and anti-interference, and large two-photon cross section (555 GM). The probe is conveniently used to detect Cl- in water samples and biological samples including human sweat, serum, and urine samples, indicating it holds great promise for chloride detection and biological application. Graphical abstract ᅟ.