Accelerating protein aggregation and amyloid fibrillation for rapid inhibitor screening.

The accumulation and deposition of amyloid fibrils, also known as amyloidosis, in tissues and organs of patients has been found to be linked to numerous devastating neurodegenerative diseases. The aggregation of proteins to form amyloid fibrils, however, is a slow pathogenic process, and is a major issue for the evaluation of the effectiveness of inhibitors in new drug discovery and screening. Here, we used microdroplet reaction technology to accelerate the amyloid fibrillation process, monitored the process to shed light on the fundamental mechanism of amyloid self-assembly, and demonstrated the value of the technology in the rapid screening of potential inhibitor drugs. Proteins in microdroplets accelerated to form fibrils in milliseconds, enabling an entire cycle of inhibitor screening for Aß40 within 3 minutes. The technology would be of broad interest to drug discovery and therapeutic design to develop treatments for diseases associated with protein aggregation and fibrillation.

Building Medication Profiles in the Elderly: a Qualitative Study Based on Medication Information Literacy in a Long-Term Care Facility.

Purpose: Long-term care facilities are increasingly challenged with meeting the diverse healthcare needs of the elderly population, particularly concerning medication management. Understanding medication information literacy and behavior among this demographic is imperative. Therefore, this qualitative study aims to explore medication information literacy and develop distinct medication profiles among elderly long-term care residents. Material and Methods: In this study, we conducted in-depth semi-structured interviews with 32 participants aged 65 or older residing in a long-term care facility. The interviews were designed to explore participants' understanding of medication information, medication management practices, and experiences with healthcare providers. Thematic analysis was employed to analyze the interview data, allowing for the identification of common patterns and themes related to medication-taking behavior among the elderly residents. Results: The thematic analysis revealed four distinct medication behavior profiles among the elderly long-term care residents: (1) Proactive Health Self-Managers, (2) Medication Information Adherents, (3) Experience-Based Medication Users, and (4) Nonadherent Medication Users. These findings provide valuable insights into the diverse approaches to medication management within long-term care facilities and underscore the importance of tailored interventions to support the specific needs of each profile. Conclusion: This study highlights the necessity for tailored medication education and support to optimize medication management for the elderly. With the aging population expansion, addressing the unique medication challenges within long-term care facilities becomes increasingly critical. This research contributes to ongoing endeavors to enhance healthcare services for the elderly, striving for safer and more effective medication-taking behavior.

Erasable and Field Programmable DNA Circuits Based on Configurable Logic Blocks.

DNA is commonly employed as a substrate for the building of artificial logic networks due to its excellent biocompatibility and programmability. Till now, DNA logic circuits are rapidly evolving to accomplish advanced operations. Nonetheless, nowadays, most DNA circuits remain to be disposable and lack of field programmability and thereby limits their practicability. Herein, inspired by the Configurable Logic Block (CLB), the CLB-based erasable field-programmable DNA circuit that uses clip strands as its operation-controlling signals is presented. It enables users to realize diverse functions with limited hardware. CLB-based basic logic gates (OR and AND) are first constructed and demonstrated their erasability and field programmability. Furthermore, by adding the appropriate operation-controlling strands, multiple rounds of programming are achieved among five different logic operations on a two-layer circuit. Subsequently, a circuit is successfully built to implement two fundamental binary calculators: half-adder and half-subtractor, proving that the design can imitate silicon-based binary circuits. Finally, a comprehensive CLB-based circuit is built that enables multiple rounds of switch among seven different logic operations including half-adding and half-subtracting. Overall, the CLB-based erasable field-programmable circuit immensely enhances their practicability. It is believed that design can be widely used in DNA logic networks due to its efficiency and convenience.

Challenges in clinical practice, biological mechanism and prospects of physical ablation therapy for COPD.

Chronic obstructive pulmonary disease (COPD) is projected to become the third leading cause of death globally by 2030. Despite the limited treatment options available for advanced COPD, which are mostly restricted to costly lung transplants, physical ablation therapy offers promising alternatives. This technique focuses on ablating lesioned airway epithelium, reducing secretions and obstructions, and promoting normal epithelial regeneration, demonstrating significant therapeutic potential. Physical ablation therapy primarily involves thermal steam ablation, cryoablation, targeted lung denervation, and high-voltage pulsed electric field ablation. These methods help transform the hypersecretory phenotype, alleviate airway inflammation, and decrease the volume of emphysematous lung segments by targeting goblet cells and damaged lung areas. Compared to traditional treatments, endoscopic physical ablation offers fewer injuries, quicker recovery, and enhanced safety. However, its application in COPD remains limited due to inconsistent clinical outcomes, a lack of well-understood mechanisms, and the absence of standardized guidelines. This review begins by exploring the development of these ablation techniques and their current clinical uses in COPD treatment. It then delves into the therapeutic effects reported in recent clinical studies and discusses the underlying mechanisms. Finally, the review assesses the future prospects and challenges of employing ablation technology in COPD clinical practice, aiming to provide a practical reference and a theoretical basis for its use and inspire further research.

Discovery of novel biphenyl derivatives as androgen receptor degraders for the treatment of enzalutamide-resistant prostate cancer.

Second-generation AR antagonists, such as enzalutamide, are the primary therapeutic agents for advanced prostate cancer. However, the development of both primary and secondary drug resistance leads to treatment failures and patient mortality. Bifunctional agents that simultaneously antagonize and degrade AR block the AR signaling pathway more completely and exhibit excellent antiproliferative activity against wild-type and drug-resistant prostate cancer cells. Here, we reported the discovery and optimization of a series of biphenyl derivatives as androgen receptor antagonists and degraders. These biphenyl derivatives exhibited potent antiproliferative activity against LNCaP and 22Rv1 cells. Our discoveries enrich the diversity of small molecule AR degraders and offer insights for the development of novel AR degraders for the treatment of enzalutamide-resistant prostate cancer.

DDX58 variant triggers IFN-ß-induced autophagy in trabecular meshwork and influences intraocular pressure.

Singleton-Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN-stimulated gene expression and high IFN-ß-based type-I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN-ß on TM cells. Our study is the first to demonstrate that IFN-ß significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN-ß remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN-ß-induced autophagy in TM cells, we performed microarray analysis in IFN-ß-treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN-ß-induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN-ß. Our findings suggest that DDX58 mutation leads to the overproduction of IFN-ß, which elevates IOP by modulating autophagy through RSAD2 in TM cells.

The Mechanism of Guerbet Reaction by Metal Ligand Cooperation.

The Guerbet reaction is important for the synthesis of longer-chain monoalcohols like isobutanol through catalytic transfer hydrogenation from short-chain methanol and ethanol. However, the mechanism becomes complicated, especially considering the variations in the different metal-ligand cooperation (MLC) catalysts used. In order to further understand the Guerbet reaction, DFT studies were performed to figure out the detailed mechanism initiated by the unique Mn-PCP MLC Catalyst. Our results suggest that even with the assistance of the carbanion site of the PCP ligand, the direct substitution mechanism is less favored than the condensation-reduction mechanism. The key step of the reaction is the final reduction of the carbonyl, in which the 1,4-reduction of the unsaturated aldehyde is prior to the 3,4-reduction or 1,2-reduction due to the stronger interaction between the catalyst and the substrate. It is found that the production of isobutanol is preferred over n-butanol because of the lower total free energy barrier and lower relative free energy of the product. Finally, by changing the electronic effect of the carbanion site of the catalyst, we found that the relation between the electronic effect and the highest free energy span was not monotonous and a point with optimal electronic effect exists numerically.

Arenethiolate-Catalyzed 1,5-HAT of Aryl Halides: Synthesis of γ-Spirolactams.

γ-Spirolactam is a privileged building block that is found in a wide range of natural products and bioactive compounds. Herein, we report an arenethiolate-catalyzed 1,5-HAT of aryl halides to obtain γ-spirolactams through a SET reduction/intramolecular 1,5-HAT/cyclization/HAT process. This protocol features metal-free conditions and a broad substrate scope, furnishing the γ-spirolactams in moderate to excellent yields. Notably, aryl bromides, aryl chlorides and even aryl fluorides are well tolerated in this transformation. A mechanism involving arenethiolate as a SET catalyst is proposed based on DFT calculation.

Electrospray-assisted cryo-EM sample preparation to mitigate interfacial effects.

Addressing interfacial effects during specimen preparation in cryogenic electron microscopy remains challenging. Here we introduce ESI-cryoPrep, a specimen preparation method based on electrospray ionization in native mass spectrometry, designed to alleviate issues associated with protein denaturation or preferred orientation induced by macromolecule adsorption at interfaces. Through fine-tuning spraying parameters, we optimized protein integrity preservation and achieved the desired ice thickness for analyzing target macromolecules. With ESI-cryoPrep, we prepared high-quality cryo-specimens of five proteins and obtained three-dimensional reconstructions at near-atomic resolution. Our findings demonstrate that ESI-cryoPrep effectively confines macromolecules within the middle of the thin layer of amorphous ice, facilitating the preparation of blotting-free vitreous samples. The protective mechanism, characterized by the uneven distribution of charged biomolecules of varying sizes within charged droplets, prevents the adsorption of target biomolecules at air-water or graphene-water interfaces, thereby avoiding structural damage to the protein particles or the introduction of dominant orientation issues.

Synthesis and Characterization of Superhydrophobic Epoxy Resin Coating with SiO2@CuO/HDTMS for Enhanced Self-Cleaning, Photocatalytic, and Corrosion-Resistant Properties.

The exceptional corrosion resistance and combined physical and chemical self-cleaning capabilities of superhydrophobic photocatalytic coatings have sparked significant interest among researchers. In this paper, we propose an economical and eco-friendly superhydrophobic epoxy resin coating that incorporates SiO2@CuO/HDTMS nanoparticles modified with Hexadecyltrimethoxysilane (HDTMS). The application of superhydrophobic coatings effectively reduces the contact area between the metal surface and corrosive media, leading to a decreased corrosion rate. Additionally, the incorporation of nanomaterials, exemplified by SiO2@CuO core-shell nanoparticles, improves the adhesion and durability of the coatings on aluminum alloy substrates. Experimental data from Tafel curve analysis and electrochemical impedance spectroscopy (EIS) confirm the superior corrosion resistance of the superhydrophobic modified aluminum alloy surface compared to untreated surfaces. Estimations indicate a significant reduction in corrosion rate after superhydrophobic treatment. Furthermore, an optical absorption spectra analysis of the core-shell nanoparticles demonstrates their suitability for photocatalytic applications, showcasing their potential contribution to enhancing the overall performance of the coated surfaces. This research underscores the promising approach of combining superhydrophobic properties with photocatalytic capabilities to develop advanced surface modification techniques for enhanced corrosion resistance and functional properties in diverse industrial settings.

Cellulose Nanofibrils of High Immunoaffinity for Efficient Enrichment of Small Extracellular Vesicles.

Extracellular vesicles (EVs), crucial in facilitating the transport of diverse molecular cargoes for intercellular communication, have shown great potential in diagnostics, therapeutics, and drug delivery. The challenge of developing effective preparation methods for EVs is heightened by their intrinsic heterogeneity and complexity. Here, a novel strategy for high EV enrichment is developed by utilizing EV-affinitive-modified cellulose nanofibrils. Specifically, modified cellulose with rich carboxyl groups has outstanding dispersing properties, able to be dispersed into cellulose nanofibrils in solution. These cellulose nanofibrils are utilized as scaffolds for the immobilization of EV-affinitive antibody of CD63 by chemical conjugation. The CD63-modified nanofibrils demonstrate a superior EV capture efficiency of 86.4% compared with other reported methods. The high performance of this system is further validated by the efficient capture of EVs from biological blood plasma, allowing the detection of bioactive markers from EV-derived miRNAs and proteins. The authors envision that these modified cellulose nanofibrils of enhanced capability on EV enrichment will open new avenues in various biomedical applications.

Automatic high-throughput and non-invasive selection of sperm at the biochemical level.

BACKGROUND: Sperm selection, a key step in assisted reproductive technology (ART), has long been restrained at the preliminary physical level (morphology or motility); however, subsequent fertilization and embryogenesis are complicated biochemical processes. Such an enormous "gap" poses tough problems for couples dealing with infertility, especially patients with severe/total asthenozoospermia . METHODS: We developed a biochemical-level, automatic-screening/separation, smart droplet-TO-hydrogel chip (BLASTO-chip) for sperm selection. The droplet can sense the pH change caused by sperm's respiration products and then transforms into a hydrogel to be selected out. FINDINGS: The BLASTO-chip system can select biochemically active sperm with an accuracy of over 90%, and its selection efficiency can be flexibly tuned by nearly 10-fold. All the substances in the system were proven to be biosafe via evaluating mice fertilization and offspring health. Live sperm down to 1% could be enriched by over 76-fold to 76%. For clinical application to patients with severe/total asthenozoospermia, the BLASTO-chip could select live sperm from human semen samples containing 10% live but 100% immotile sperm. The rates of fertilization, cleavage, early embryos, and blastocysts were drastically elevated from 15% to 70.83%, 10% to 62.5%, 5% to 37.5%, and 0% to 16.67%, respectively. CONCLUSIONS: The BLASTO-chip represents a real biochemical-level technology for sperm selection that is completely independent of sperm's motility. It can be a powerful tool in ART, especially for patients with severe/total asthenozoospermia. FUNDING: This work was funded by the Ministry of Science and Technology of China, the Ministry of Education of China, and the Shenzhen-Hong Kong Hetao Cooperation Zone.

Insights into the response of electroactive biofilm with petroleum hydrocarbons degradation ability to quorum sensing signals.

Bioelectrochemical technologies based on electroactive biofilms (EAB) are promising for petroleum hydrocarbons (PHs) remediation as anode can serve as inexhaustible electron acceptor. However, the toxicity of PHs might inhibit the formation and function of EABs. Quorum sensing (QS) is ideal for boosting the performance of EABs, but its potential effects on reshaping microbial composition of EABs in treating PHs are poorly understood. Herein, two AHL signals, C4-HSL and C12-HSL, were employed to promote EABs for PHs degradation. The start-times of AHL-mediated EABs decreased by 18-26%, and maximum current densities increased by 28-63%. Meanwhile, the removal of total PHs increased to over 90%. AHLs facilitate thicker and more compact biofilm as well as higher viability. AHLs enhanced the electroactivity and direct electron transfer capability. The total abundance of PH-degrading bacteria increased from 52.05% to 75.33% and 72.02%, and the proportion of electroactive bacteria increased from 26.14% to 62.72% and 63.30% for MFC-C4 and MFC-C12. Microbial networks became more complex, aggregated, and stable with addition of AHLs. Furthermore, AHL-stimulated EABs showed higher abundance of genes related to PHs degradation. This work advanced our understanding of AHL-mediated QS in maintaining the stable function of microbial communities in the biodegradation process of petroleum hydrocarbons.

Platelet Membrane-Coated r-SAK Improves Thrombolytic Efficacy by Targeting Thrombus.

Thrombolytic therapy is one of the most effective treatments for thrombus dissolution and recanalization of blocked vessels in thrombotic diseases. However, the application of the thrombolytic strategy has been limited due to unsatisfactory thrombolytic efficacy, relatively higher bleeding complications, and consequently restricted indications. Recombinant staphylokinase (r-SAK) is a third-generation thrombolytic agent produced by genetic engineering technology, which exhibits a better thrombolytic efficacy than urokinase and recombinant streptokinase. Inspired by the natural affinity of platelets in hemostasis and pathological thrombosis, we developed a platelet membrane (PM)-coated r-SAK (PM-r-SAK). Results from animal experiments and human in vitro studies showed that the PM-r-SAK had a thrombolytic efficacy equal to or better than its 4-fold dose of r-SAK. In a totally occluded rabbit femoral artery thrombosis model, the PM-r-SAK significantly shortened the initial recanalization time compared to the same dose and 4-fold dose of r-SAK. Regarding the recanalized vessels, the PM-r-SAK prolonged the time of reperfusion compared to the same dose and 4-fold dose of r-SAK, though the differences were not significant. An in vitro thrombolytic experiment demonstrated that the thrombolytic efficacy of PM-r-SAK could be inhibited by platelet-poor plasma from patients taking aspirin and ticagrelor. PM coating significantly improves the thrombolytic efficacy of r-SAK, which is related to the thrombus-targeting activity of the PM-r-SAK and can be inhibited by aspirin- and ticagrelor-treated plasma.

The Application of Bilayer Heterogeneous MOFs in pH and Heat-Triggered Systems for Controllable Fragrance Release.

To facilitate the integration of a fragrance encapsulation system into different products to achieve effective releases, a dual-responsive release system with pH and thermal trigger control is designed in this work. A series of ZIF-8 (M) and bilayer ZIF-8-on-ZIF-8 (MM) materials are synthesized by a solvent method at room temperature. The fragrance is encapsulated into the ZIFs by dynamic adsorption or in situ encapsulation combined dynamic adsorption. The fragrance loading contributed by dynamic adsorption was as high as 80%. The fragrance loaded in the double-layer MM host was almost twice that of the monolayer host M due to the stronger electrostatic interaction between MM and vanillin. In the pH and thermal trigger response release experiments, the second MOF layer in the MM host, as a controlled entity, greatly improved the load and kinetic equilibrium time of vanillin, and realized the controlled release of guest molecules. The developed dual-responsive release system in this work exhibits great potential in daily chemical products.

InCl3/TfOH-Mediated Convenient Synthesis of 3-Alkylideneoxindoles from 2-Oxindoles with 1,3-Diones, Ketones, or Aldehydes.

Two efficient and convenient methods for the synthesis of 3-alkylideneoxindoles are described in this paper. The InCl3/TfOH-mediated tandem Knoevenagel condensation-deacylation sequence of various 2-oxindoles with 1,3-diones or acetoacetate furnished 3-alkylideneoxindoles in satisfactory to excellent yields (up to >99% yield). Employing the reaction system, the condensation of 2-oxindoles with ketones or aldehydes also proceeded smoothly to produce 3-alkylideneoxindoles. This protocol can be amenable to scale up. The effect of acids on this condensation reaction and intermolecular competition experiments were investigated to understand the aspect of the reaction.

Fathers' needs of breastfeeding support: Perspective of health nurses.

PURPOSE: To explore the improvement of health education on father's participation in breastfeeding from the perspective of maternal and child health nurses. METHODS: Qualitative phenomenological research was used, and 15 maternal and child health nurses who provided breastfeeding support were invited. With semi-structured deep interviews and on-site recordings, data were analyzed through content analysis. RESULTS: Four main themes were extracted, including 'cultivating fathers' awareness of participation in breastfeeding', 'collaboration of multiple disciplines to improve health education on breastfeeding for fathers in hospital', 'Simulated scenarios to develop fathers' skills in solving breastfeeding problems', and 'establishing a hospital-community interface network to improve breastfeeding continuation care after hospital discharge'. CONCLUSIONS: Medical and health care departments should attach importance to guidance on health education for fathers' breastfeeding participation, cultivate fathers' awareness of participation in breastfeeding, provide multi-disciplinary collaboration-based health education on breastfeeding for fathers from the prenatal period and improve post-discharge health education on breastfeeding. The additional education being suggested would contribute to fathers being able to play an important role in breastfeeding.

Self-supervised pre-training for joint optic disc and cup segmentation via attention-aware network.

Image segmentation is a fundamental task in deep learning, which is able to analyse the essence of the images for further development. However, for the supervised learning segmentation method, collecting pixel-level labels is very time-consuming and labour-intensive. In the medical image processing area for optic disc and cup segmentation, we consider there are two challenging problems that remain unsolved. One is how to design an efficient network to capture the global field of the medical image and execute fast in real applications. The other is how to train the deep segmentation network using a few training data due to some medical privacy issues. In this paper, to conquer such issues, we first design a novel attention-aware segmentation model equipped with the multi-scale attention module in the pyramid structure-like encoder-decoder network, which can efficiently learn the global semantics and the long-range dependencies of the input images. Furthermore, we also inject the prior knowledge that the optic cup lies inside the optic disc by a novel loss function. Then, we propose a self-supervised contrastive learning method for optic disc and cup segmentation. The unsupervised feature representation is learned by matching an encoded query to a dictionary of encoded keys using a contrastive technique. Finetuning the pre-trained model using the proposed loss function can help achieve good performance for the task. To validate the effectiveness of the proposed method, extensive systemic evaluations on different public challenging optic disc and cup benchmarks, including DRISHTI-GS and REFUGE datasets demonstrate the superiority of the proposed method, which can achieve new state-of-the-art performance approaching 0.9801 and 0.9087 F1 score respectively while gaining 0.9657 D C disc and 0.8976 D C cup . The code will be made publicly available.