The codriven assembly of molecular metalla-links ([Formula: see text], [Formula: see text]) and metalla-knots ([Formula: see text], [Formula: see text]) via coordination and noncovalent interactions.

Although mechanically interlocked molecules (MIMs) display unique properties and functions associated with their intricate connectivity, limited assembly strategies are available for their synthesis. Herein, we presented a synergistic assembly strategy based on coordination and noncovalent interactions (π-π stacking and CH⋯π interactions) to selectively synthesize molecular closed three-link chains ([Formula: see text] links), highly entangled figure-eight knots ([Formula: see text] knots), trefoil knot ([Formula: see text] knot), and Borromean ring ([Formula: see text] link). [Formula: see text] links can be created by the strategic assembly of nonlinear multicurved ligands incorporating a furan or phenyl group with the long binuclear half-sandwich organometallic Cp*RhIII (Cp* = η5-pentamethylcyclopentadienyl) clip. However, utilizing much shorter binuclear Cp*RhIII units for union with the 2,6-naphthyl-containing ligand led to a [Formula: see text] knot because of the increased π-π stacking interactions between four consecutive stacked layers and CH⋯π interactions. Weakening such π-π stacking interactions resulted in a [Formula: see text] knot. The universality of this synergistic assembly strategy for building [Formula: see text] knots was verified by utilizing a 1,5-naphthyl-containing ligand. Quantitative conversion between the [Formula: see text] knot and the simple macrocycle species was accomplished by adjusting the concentrations monitored by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Furthermore, increasing the stiff π-conjugated area of the binuclear unit afforded molecular Borromean ring, and this topology is a topological isomer of the [Formula: see text] link. These artificial metalla-links and metalla-knots were confirmed by single-crystal X-ray diffraction, NMR and ESI-MS. The results offer a potent strategy for building higher-order MIMs and emphasize the critical role that noncovalent interactions play in creating sophisticated topologies.

The kpc-1 3'UTR facilitates dendritic transport and translation efficiency of mRNAs for dendrite arborization of a mechanosensory neuron important for male courtship.

A recently reported Schizophrenia-associated genetic variant in the 3'UTR of the human furin gene, a homolog of C. elegans kpc-1, highlights an important role of the furin 3'UTR in neuronal development. We isolate three kpc-1 mutants that display abnormal dendrite arborization in PVD neurons and defective male mating behaviors. We show that the kpc-1 3'UTR participates in dendrite branching and self-avoidance. The kpc-1 3'UTR facilitates mRNA localization to branching points and contact points between sibling dendrites and promotes translation efficiency. A predicted secondary structural motif in the kpc-1 3'UTR is required for dendrite self-avoidance. Animals with over-expression of DMA-1, a PVD dendrite receptor, exhibit similar dendrite branching and self-avoidance defects that are suppressed with kpc-1 over-expression. Our results support a model in which KPC-1 proteins are synthesized at branching points and contact points to locally down-regulate DMA-1 receptors to promote dendrite branching and self-avoidance of a mechanosensory neuron important for male courtship.

Threshold of hyperglycaemia associated with mortality in critically ill patients: a multicentre, prospective, observational study using continuous glucose monitoring.

AIMS/HYPOTHESIS: Continuous glucose monitoring (CGM) provides comprehensive information on the exposure to dysglycaemia. This study aimed to investigate the threshold of hyperglycaemia related to mortality risk in critically ill patients using CGM technology. METHODS: A total of 293 adult critically ill patients admitted to intensive care units of five medical centres were prospectively included between May 2020 and November 2021. Participants wore intermittently scanned CGM for a median of 12.0 days. The relationships between different predefined time above ranges (TARs), with the thresholds of hyperglycaemia ranging from 7.8 to 13.9 mmol/l (140-250 mg/dl), and in-hospital mortality risk were assessed by multivariate Cox proportional regression analysis. Time in ranges (TIRs) of 3.9 mmol/l (70 mg/dl) to the predefined hyperglycaemic thresholds were also assessed. RESULTS: Overall, 66 (22.5%) in-hospital deaths were identified. Only TARs with a threshold of 10.5 mmol/l (190 mg/dl) or above were significantly associated with the risk of in-hospital mortality, after adjustment for covariates. Furthermore, as the thresholds for TAR increased from 10.5 mmol/l to 13.9 mmol/l (190 mg/dl to 250 mg/dl), the hazards of in-hospital mortality increased incrementally with every 10% increase in TARs. Similar results were observed concerning the associations between TIRs with various upper thresholds and in-hospital mortality risk. For per absolute 10% decrease in TIR 3.9-10.5 mmol/l (70-190 mg/dl), the risk of in-hospital mortality was increased by 12.1% (HR 1.121 [95% CI 1.003, 1.253]). CONCLUSIONS/INTERPRETATION: A glucose level exceeding 10.5 mmol/l (190 mg/dl) was significantly associated with higher risk of in-hospital mortality in critically ill patients.

The Topological Transformation of Trefoil Knots to Solomon Links via Diels-Alder Click Reaction.

The quest for more efficient, user-friendly, and less wasteful topological transformations remains a significant challenge in the realm of postassembly modifications. In this article, high yields of two molecular trefoil knots (Rh-1, Ir-1) were obtained using ligand 3,6-bis(3-(pyridin-4-yl)phenyl)-1,2,4,5-tetrazine (L1) with reactive tetrazine units and binuclear half-sandwich organometallic units [Cp*2M2(µ-TPPHZ)(OTf)2](OTf)2 (Rh-B, M = RhIII; Ir-B, M = IrIII). 2,5-Norbornadiene was used as an inducer of the Diels-Alder click reaction to modulate rapidly and efficiently the transformation of Trefoil knots to Solomon links. However, the key to achieving this topological structural change is the subtle increase in site steric of the pyridazine fragments (L2), which allows the molecular structures to spread and bend in three-dimensional space, as confirmed by single-crystal X-ray diffraction, ESI-TOF/MS, elementary analysis and detailed solution-state NMR techniques.

Two-sample Mendelian randomization analysis reveals causal relationships between blood lipids and venous thromboembolism.

Venous Thromboembolism (VTE) is a complex disease that can be classified into two subtypes: Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). Previous observational studies have shown associations between lipids and VTE, but causality remains unclear. Hence, by utilizing 241 lipid-related traits as exposures and data from the FinnGen consortium on VTE, DVT, and PE as outcomes, we conducted two-sample Mendelian randomization (MR) analysis to investigate causal relationships between lipids and VTE, DVT and PE. The MR results identified that fatty acid (FA) unsaturation traits (Ratio of bis-allylic bonds to double bonds in lipids, and Ratio of bis-allylic bonds to total fatty acids in lipids) were associated with VTE (OR [95% CI]: 1.21 [1.15-1.27]; 1.21 [1.13-1.30]), DVT (OR [95%CI]: 1.24 [1.16-1.33]; 1.26 [1.16-1.36]) and PE (OR [95%CI]: 1.18 [1.08-1.29]; 1.18 [1.09-1.27]). Phosphatidylcholines exhibit potential causal effects on VTE and PE. Phosphatidylcholine acyl-alkyl C40:4 (PC ae C40:4) was negatively associated with VTE (OR [95% CI]: 0.79 [0.73-0.86]), while phosphatidylcholine diacyl C42:6 (PC aa C42:6) and phosphatidylcholine acyl-alkyl C36:4 (PC ae C36:4) were positively associated with PE (OR [95%CI]: 1.44 [1.20-1.72]; 1.22 [1.10-1.35]). Additionally, we found that medium LDL had a protective effect on VTE. Our study indicates that higher FA unsaturation may increase the risk of VTE, DVT, and PE. Different types of phosphatidylcholine have either promotive or inhibitory effects on VTE and PE, contributing to a better understanding of the risk factors for VTE.

Small Scale, Big Impact: Nanotechnology-Enhanced Drug Delivery for Brain Diseases.

Central nervous system (CNS) diseases, ranging from brain cancers to neurodegenerative disorders like dementia and acute conditions such as strokes, have been heavily burdening healthcare and have a direct impact on patient quality of life. A significant hurdle in developing effective treatments is the presence of the blood-brain barrier (BBB), a highly selective barrier that prevents most drugs from reaching the brain. The tight junctions and adherens junctions between the endothelial cells and various receptors expressed on the cells make the BBB form a nonfenestrated and highly selective structure that is crucial for brain homeostasis but complicates drug delivery. Nanotechnology offers a novel pathway to circumvent this barrier, with nanoparticles engineered to ferry drugs across the BBB, protect drugs from degradation, and deliver medications to the designated area. After years of development, nanoparticle optimization, including sizes, shapes, surface modifications, and targeting ligands, can enable nanomaterials tailored to specific brain drug delivery settings. Moreover, smart nano drug delivery systems can respond to endogenous and exogenous stimuli that control subsequent drug release. Here, we address the importance of the BBB in brain disease treatment, summarize different delivery routes for brain drug delivery, discuss the cutting-edge nanotechnology-based strategies for brain drug delivery, and further offer valuable insights into how these innovations in nanoparticle technology could revolutionize the treatment of CNS diseases, presenting a promising avenue for noninvasive, targeted therapeutic interventions.

Deep Learning-Assisted Two-Dimensional Transperineal Ultrasound for Analyzing Bladder Neck Motion in Women With Stress Urinary Incontinence.

BACKGROUND: No universally recognized transperineal ultrasound parameters are available for evaluating stress urinary incontinence. The information captured by commonly used perineal ultrasound parameters is limited and insufficient for a comprehensive assessment of stress urinary incontinence. Although bladder neck motion plays a major role in stress urinary incontinence, objective and visual methods to evaluate its impact on stress urinary incontinence remain lacking. OBJECTIVE: To use a deep learning-based system to evaluate bladder neck motion using two-dimensional transperineal ultrasound videos, exploring motion parameters for diagnosing and evaluating stress urinary incontinence. We hypothesized that bladder neck motion parameters are associated with stress urinary incontinence and are useful for stress urinary incontinence diagnosis and evaluation. STUDY DESIGN: This retrospective study including 217 women involved the following parameters: maximum and average speeds of bladder neck descent, ß angle, urethral rotation angle, and duration of the Valsalva maneuver. The fitted curves were derived to visualize bladder neck motion trajectories. Comparative analyses were conducted to assess these parameters between stress urinary incontinence and control groups. Logistic regression and receiver operating characteristic curve analyses were employed to evaluate the diagnostic performance of each motion parameter and their combinations for stress urinary incontinence. RESULTS: Overall, 173 women were enrolled in this study (82, stress urinary incontinence group; 91, control group). No significant differences were observed in the maximum and average speeds of bladder neck descent and in the speed variance of bladder neck descent. The maximum and average speed of the ß and urethral rotation angles were faster in the stress urinary incontinence group than in the control group (151.2 vs 109.0 mm/s, P=0.001; 6.0 vs 3.1 mm/s, P <0.001; 105.5 vs 69.6 mm/s, P <0.001; 10.1 vs 7.9 mm/s, P=0.011, respectively). The speed variance of the ß and urethral rotation angles were higher in the stress urinary incontinence group (844.8 vs 336.4, P <0.001; 347.6 vs 131.1, P <0.001, respectively). The combination of the average speed of the ß angle, maximum speed of the urethral rotation angle, and duration of the Valsalva maneuver demonstrated a strong diagnostic performance (area under the curve, 0.87). When 0.481*ß anglea + 0.013*URAm + 0.483*Dval = 7.405, the diagnostic sensitivity was 70% and specificity was 92%, highlighting the significant role of bladder neck motion in stress urinary incontinence, particularly changes in the speed of the ß and urethral rotation angles. CONCLUSIONS: A system utilizing deep learning can describe the motion of the bladder neck in women with stress urinary incontinence during the Valsalva maneuver, making it possible to visualize and quantify bladder neck motion on transperineal ultrasound. The speeds of the ß and urethral rotation angles and duration of the Valsalva maneuver were relatively reliable diagnostic parameters.

Further structural optimization and SAR study of sungsanpin derivatives as cell-invasion inhibitors.

Metastasis is one of the major causes of death in patients with cancer, and cell invasion plays a fundamental part in this process. Because of the absence of efficacious treatments, caring for these patients is challenging. Recently, we optimized the structure of the naturally occurring lasso peptide sungsanpin. We identified two peptides, octapeptide S3 and cyclic peptide S4, which inhibited invasion into A549 cells effectively. We undertook an alanine scan of S3 to explore the structure-activity relationship. The linear octapeptide S3-4 and cyclic peptide S4-1 exhibited improved inhibition of invasion into A549 cells. We modified S3-4 to obtain S3-4K, which displayed much higher inhibitory activity against invasion into A549 cells than S3-4. Of all peptides tested, S4-1 upregulated significantly mRNA of tissue inhibitor matrix metalloproteinase TIMP-1 and TIMP-2.

Factors Influencing Plasma Concentrations of Valproic Acid in Pediatric Patients With Epilepsy and the Clinical Significance of CYP2C9 Genotypes in Personalized Valproic Acid Therapy.

BACKGROUND: The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing. METHODS: The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR. RESULTS: The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes ( P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV. CONCLUSIONS: Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy.

Controlled Assembly of a Dawson-like Antimoniotungstate-Supported Trefoil-type Trimer with Good Proton Conductivity Performance.

With the excellent properties of POM in the field of proton conductivity, the preparation of POM-based proton-conductive materials has burst into life. Herein, an unprecedented Sb-templated all-inorganic trimer Na8H18.64[(SbW14O52)3(Sb2W6.12Ru5.88O18)]·85H2O (1), which is based on tetravacant Dawson-like [SbW14O52]17- blocks and exhibits a trefoil type with D3 symmetry, has been successfully designed and synthesized by the assembly of simple materials with a one-pot hydrothermal method under acidic conditions. Also, compound 1 is systematically characterized by single-crystal X-ray diffraction, PXRD, ESI-MS, IR spectroscopy, UV-vis, elemental analysis, and TGA. Crystal structure data analysis demonstrates that compound 1 is constructed by a hexagonal prismatic heterometallic {Sb2W6.12Ru5.88O18} core and three equivalent {SbW14} units bridged through µ2-O atoms in periphery. Subsequently, further property experiments show that compound 1 exhibits high proton conductivity with a conductivity value (σ) of 3.07 × 10-2 S cm-1 at 75 °C and 80% relative humidity (RH). The activation energy of compound 1 evaluated by the Arrhenius plots is 0.22 eV, which indicates that the Grotthuss mechanism is dominant during the process of proton transfer.

Characteristics of the time processing of adults' strongest sustained attentional bias toward neutral infant faces.

Previous studies have shown that adults exhibit the strongest attentional bias toward neutral infant faces when viewing faces with different expressions at different attentional processing stages due to different stimulus presentation times. However, it is not clear how the characteristics of the temporal processing associated with the strongest effect change over time. Thus, we combined a free-viewing task with eye-tracking technology to measure adults' attentional bias toward infant and adult faces with happy, neutral, and sad expressions of the same face. The results of the analysis of the total time course indicated that the strongest effect occurred during the strategic processing stage. However, the results of the analysis of the split time course revealed that sad infant faces first elicited adults' attentional bias at 0 to 500 ms, whereas the strongest effect of attentional bias toward neutral infant faces was observed at 1000 to 3000 ms, peaking at 1500 to 2000 ms. In addition, women and men had no differences in their responses to different expressions. In summary, this study provides further evidence that adults' attentional bias toward infant faces across stages of attention processing is modulated by expressions. Specifically, during automatic processing adults' attentional bias was directed toward sad infant faces, followed by a shift to the processing of neutral infant faces during strategic processing, which ultimately resulted in the strongest effect. These findings highlight that this strongest effect is dynamic and associated with a specific time window in the strategic process.

Synergizing Steric Hindrance and Stacking Interactions To Facilitate the Controlled Assembly of Multiple 41 Metalla-Knots and Pseudo-Solomon Links.

In this work, a noncoplanar terphenyl served as a building block to synthesize a novel 3,3'-substituted bipyridyl ligand (L1) which further reacted with binuclear half-sandwich units A/B, giving rise to two aesthetic 41 metalla-knots in high yields via a coordination-driven self-assembly strategy. Furthermore, given the inherent compactness of the 41 metalla-knots, it creates favorable conditions for the emergence of steric repulsion. We focused on progressively introducing nitrogen atoms featuring a lone pair of electrons (LPEs) into ligand L1 to manipulate the balance of H⋅⋅⋅H/LPEs⋅⋅⋅LPEs steric repulsion during the assembly process, ultimately achieving controlled assembly from 41 metalla-knots to the pseudo-Solomon link and then to molecular tweezer-like assembly facilitated by stacking interactions. All the assemblies were well characterized by solution-state NMR techniques, ESI-TOF/MS, and single-crystal X-ray diffraction. The evolutionary process of the topological architectures is equivalent to visualizing the synergistic effect of steric hindrance and stacking interactions on structural assembly, providing a new avenue for achieving the controlled synthesis of different topologies.

Cell Membrane Camouflaged Biomimetic Nanoparticles as a Versatile Platform for Brain Diseases Treatment.

Although there are various advancements in biomedical in the past few decades, there are still challenges in the treatment of brain diseases. The main difficulties are the inability to deliver a therapeutic dose of the drug to the brain through the blood-brain barrier (BBB) and the serious side effects of the drug. Thus, it is essential to select biocompatible drug carriers and novel therapeutic tools to better enhance the effect of brain disease treatment. In recent years, biomimetic nanoparticles (BNPs) based on natural cell membranes, which have excellent biocompatibility and low immunogenicity, are widely used in the treatment of brain diseases to enable the drug to successfully cross the BBB and target brain lesions. BNPs can prolong the circulation time in vivo, are more conducive to drug aggregation in brain lesions. Cell membranes (CMs) from cancer cells (CCs), red blood cells (RBCs), white blood cells (WBCs), and so on are used as biomimetic coatings for nanoparticles (NPs) to achieve the ability to target, evade clearance, or stimulate the immune system. This review summarizes the application of different cell sources as BNPs coatings in the treatment of brain diseases and discusses the possibilities and challenges of clinical translation.

Assessing the relative effectiveness of various ultrasound-guided ablation techniques for treating benign thyroid nodules: A systematic review and network meta-analysis.

BACKGROUND: Benign thyroid nodules (BTNs) represent a prevalent clinical challenge globally, with various ultrasound-guided ablation techniques developed for their management. Despite the availability of these methods, a comprehensive evaluation to identify the most effective technique remains absent. This study endeavors to bridge this knowledge gap through a network meta-analysis (NMA), aiming to enhance the understanding of the comparative effectiveness of different ultrasound-guided ablation methods in treating BTNs. METHODS: We comprehensively searched PubMed, Embase, Cochrane, Web of Science, Ovid, SCOPUS, and ProQuest for studies involving 16 ablation methods, control groups, and head-to-head trials. NMA was utilized to evaluate methods based on the percentage change in nodule volume, symptom score, and cosmetic score. This study is registered in INPLASY (registration number 202260061). RESULTS: Among 35 eligible studies involving 5655 patients, NMA indicated that RFA2 (radiofrequency ablation, 2 sessions) exhibited the best outcomes at 6 months for percentage change in BTN volume (SUCRA value 74.6), closely followed by RFA (SUCRA value 73.7). At 12 months, RFA was identified as the most effective (SUCRA value 81.3). Subgroup analysis showed RFA2 as the most effective for solid nodule volume reduction at 6 months (SUCRA value 75.6), and polidocanol ablation for cystic nodules (SUCRA value 66.5). CONCLUSION: Various ablation methods are effective in treating BTNs, with RFA showing notable advantages. RFA with 2 sessions is particularly optimal for solid BTNs, while polidocanol ablation stands out for cystic nodules.

In-situ texturing hollow carbon host anchored with Fe single atoms accelerating solid-phase redox for Li-Se batteries.

Se-based cathodes have caught tremendous attention owing to their comparable volumetric capacity and better electronic conductivity to S cathodes. However, its low utilization ratio and sluggish redox kinetics due to the high reaction barrier of solid-phase transformation from Se to Li2Se limit its practical application. Herein, an in-situ texturing hollow carbon host by gas-solid interface reaction anchored with Fe single-atomic catalyst is designed and prepared for advanced Li-Se batteries. This Se host presents high pore volume of 1.49 cm3 g-1, Fe single atom content of 1.53 wt%, and its specific structure protects single-atomic catalyst from the destructive reaction environment, thus balancing catalytic activity and durability. After Se loading by reduction of H2SeO3, this homogenous Se-based cathode delivers a superior rate capacity of 431.3 mA h g-1 at 4C, and great discharge capacity of 301.8 mA h g-1 after 1000 cycles at 10C, with high Li-ion diffusion coefficient and capacitance-contributed ratio. The distribution of relaxation times analysis verifies solid-phase transformation mechanism of this cathode and density functional theory calculations confirm the adsorption and bidirectionally catalysis effect of Fe single-atomic catalyst. This work provides a new strategy to prepare high-efficient Se cathode associated with non-noble metal single atoms for high-performance Li-Se batteries.

Laser-Induced Preparation of Anderson-Type Polyoxometalate-Derived Sulfide/Oxide Electrocatalysts for Electrochemical Water Oxidation.

Developing cost-effective and high-active electrocatalysts is vital to enhance the electrocatalytic performance for oxygen evolution reaction (OER). However, traditional pyrolysis methods require complicated procedures, exact temperatures, and long reaction times, leading to high costs and low yields of electrocatalysts in potential industrial applications. Herein, a rapid and economic laser-induced preparation strategy is proposed to synthesize three bimetallic sulfide/oxide composites (MMoOS, M=Fe, Co, and Ni) on a nickel foam (NF) substrate. A focused CO2 laser with high energy is applied to decompose Anderson-type polyoxometalate (POM)-based precursors, enabling the creation of abundant heteropore and defective structures in the MMoOS composites that have multi-components of MS/Mo4O11/MoS2. Remarkably, owing to the structural interactions between the active species, FeMoOS shows superior electrocatalytic performance for OER in an alkaline medium, exhibiting a low overpotential of 240 mV at 50 mA cm-2, a small Tafel slope of 79 mV dec-1, and good durability for 80 h. Physical characterizations after OER imply that partially dissolved Mo-based species and new-formed NiO/NiOOH can effectively uncover abundant active sites, fasten charge transfer, and modify defective structures. This work provides a rapid laser-induced irradiation method for the synthesis of POM-derived nanocomposites as promoted electrocatalysts.

Engineering Nanomedicine for Non-Viral RNA-Based Gene Therapy of Glioblastoma.

Glioblastoma multiforme (GBM) is the most common type of malignant tumor of the central nervous system, characterized by aggressiveness, genetic instability, heterogenesis, and unpredictable clinical behavior. Disappointing results from the current clinical therapeutic methods have fueled a search for new therapeutic targets and treatment modalities. GBM is characterized by various genetic alterations, and RNA-based gene therapy has raised particular attention in GBM therapy. Here, we review the recent advances in engineered non-viral nanocarriers for RNA drug delivery to treat GBM. Therapeutic strategies concerning the brain-targeted delivery of various RNA drugs involving siRNA, microRNA, mRNA, ASO, and short-length RNA and the therapeutical mechanisms of these drugs to tackle the challenges of chemo-/radiotherapy resistance, recurrence, and incurable stem cell-like tumor cells of GBM are herein outlined. We also highlight the progress, prospects, and remaining challenges of non-viral nanocarriers-mediated RNA-based gene therapy.

Growth and yield of maize in response to reduced fertilizer application and its impacts on population dynamics and community biodiversity of insects and soil microbes.

In the North China Plain, farmers are using excessive amounts of fertilizer for the production of high-yield crop yield, which indirectly causes pollution in agricultural production. To investigate an optimal rate of fertilizer application for summer maize, the fertilizer reduction experiments with 600 kg/ha NPK (N: P2O5: K2O = 28: 8: 10) as normal fertilizer application (NFA), (i.e., 100F), were conducted successively during 2020 and 2021 to study the effects of reduced fertilizer rates, including 90% (540 kg/ha; i.e., 90F), 80% (480 kg/ha; i.e., 80F), 62.5% (375 kg/ha; i.e., 62.5F) and 50% (300 kg/ha; i.e., 50F) of NFA, on the plant growth of maize, the dynamics of key population abundances and community diversity of insects, and the composition and diversity of microbial community and finally to find out the N-metabolic enzymes' activity in soil. Our findings revealed that the fertilizer reduction rates by 10% - 20% compared to the current 100% NFA, and it has not significantly affected the plant growth of maize, not only plant growth indexes but also foliar contents of nutrients, secondary metabolites, and N-metabolic enzymes' activity. Further, there was no significant alteration of the key population dynamics of the Asian corn borer (Ostrinia furnacalis) and the community diversity of insects on maize plants. It is interesting to note that the level of N-metabolic enzymes' activity and microbial community diversity in soil were also not affected. While the fertilizer reduction rate by 50% unequivocally reduced field corn yield compared to 100% NFA, significantly decreased the yield by 17.10%. The optimal fertilizer application was calculated as 547 kg/ha (i.e., 91.17% NFA) based on the simulation analysis of maize yields among the five fertilizer application treatments, and the fertilizer application reduced down to 486 kg/ha (i.e., 81.00% NFA) with a significant reduction of maize yield. These results indicated that reduced the fertilizer application by 8.83% - 19.00% is safe and feasible to mitigate pollution and promote sustainable production of maize crops in the region.

Horizontal gene transfer plays a crucial role in the development of antibiotic resistance in an antibiotic-free shrimp farming system.

Antibiotic selective pressure in aquaculture systems often results in the antibiotic resistance genes (ARGs) proliferation. Nonetheless, a paucity of data exists concerning the mechanisms of ARGs development in aquaculture systems without the influences of antibiotics. This study utilized metagenomic approaches to elucidate the dynamics and transfer mechanisms of ARGs throughout the aquaculture of Pacific white shrimp. A marked change in the resistome was observed throughout the aquaculture without antibiotics. The total ARGs relative abundance increased from 0.05 to 0.33 by day 90 of cultivation, with even higher in mixed wastewater (0.44). Both bacterial communities and mobile genetic elements play pivotal roles in the development of ARGs. Metagenome-assembled genomes showed enrichment of environmentally intrinsic ARGs on chromosomes including macB and mdtK. The plasmid-mediated horizontal transfer was recognized as a principal factor contributing to the rise of ARGs, particularly for tetG and floR, and this led to an escalation of resistance risk, peaking at a risks core of 35.43 on day 90. This study demonstrates that horizontal gene transfer plays a crucial role in ARGs development without antibiotic pressure, which can provide a theoretical foundation for controlling ARGs proliferation in aquaculture systems.

Cyclic Peptide Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Design, Synthesis, and In Vivo Treatment of Acute Lung Injury.

Directly blocking the Keap1-Nrf2 pathway is a promising strategy for the mitigation of acute lung injury (ALI). Peptide Keap1-Nrf2 inhibitors have been reported to have a high Keap1 binding affinity. However, these inhibitors showed weak activity in cells and/or animals. In this study, we designed a series of linear peptides from an Nrf2-based 9-mer Ac-LDEETGEFL-NH2. To improve the cellular activity, we further designed cyclic peptides based on the crystal complex of Keap1 with a linear peptide. Among them, cyclic 9-mer ZC9 targeting Keap1 showed a better affinity (KD2 = 51 nM). Specifically, it exhibited an acceptable water solubility (>38 mg/mL), better cell permeability, cell activity, and metabolic stability (serum t1/2 > 24 h). In the in vitro LPS-induced oxidative damages and ALI model, ZC9 showed significant dose-response reversal activity without apparent toxicity. In conclusion, our results suggested ZC9 as a lead cyclic peptide targeting the Keap1-Nrf2 pathway for ALI clinical treatment.