The immune-evasive proline-283 substitution in influenza nucleoprotein increases aggregation propensity without altering the native structure.

Nucleoprotein (NP) is a key structural protein of influenza ribonucleoprotein complexes and is central to viral RNA packing and trafficking. NP also determines the sensitivity of influenza to myxovirus resistance protein 1 (MxA), an innate immunity factor that restricts influenza replication. A few critical MxA-resistant mutations have been identified in NP, including the highly conserved proline-283 substitution. This essential proline-283 substitution impairs influenza growth, a fitness defect that becomes particularly prominent at febrile temperature (39°C) when host chaperones are depleted. Here, we biophysically characterize proline-283 NP and serine-283 NP to test whether the fitness defect is caused by the proline-283 substitution introducing folding defects. We show that the proline-283 substitution changes the folding pathway of NP, making NP more aggregation prone during folding, but does not alter the native structure of the protein. These findings suggest that influenza has evolved to hijack host chaperones to promote the folding of otherwise biophysically incompetent viral proteins that enable innate immune system escape.

Liver kinase B-1 modulates the activity of dopamine neurons in the ventral tegmental area and regulates social memory formation.

Social memory is the ability to discriminate between familiar and unknown conspecifics. It is an important component of social cognition and is therefore essential for the establishment of social relationships. Although the neural circuit mechanisms underlying social memory encoding have been well investigated, little focus has been placed on the regulatory mechanisms of social memory processing. The dopaminergic system, originating from the midbrain ventral tegmental area (VTA), is a key modulator of cognitive function. This study aimed to illustrate its role in modulating social memory and explore the possible molecular mechanisms. Here, we show that the activation of VTA dopamine (DA) neurons is required for the formation, but not the retrieval, of social memory. Inhibition of VTA DA neurons before social interaction, but not 24 h after social interaction, significantly impaired social discrimination the following day. In addition, we showed that the activation of VTA DA neurons was regulated by the serine/threonine protein kinase liver kinase B1 (Lkb1). Deletion of Lkb1 in VTA DA neurons reduced the frequency of burst firing of dopaminergic neurons. Furthermore, Lkb1 plays an important role in regulating social behaviors. Both genetic and virus-mediated deletions of Lkb1 in the VTA of adult mice impaired social memory and subsequently attenuated social familiarization. Altogether, our results provide direct evidence linking social memory formation to the activation of VTA DA neurons in mice and illustrate the crucial role of Lkb1 in regulating VTA DA neuron function.

A Novel DNA Synthesis Platform Design with High-Throughput Paralleled Addressability and High-Density Static Droplet Confinement.

Using DNA as the next-generation medium for data storage offers unparalleled advantages in terms of data density, storage duration, and power consumption as compared to existing data storage technologies. To meet the high-speed data writing requirements in DNA data storage, this paper proposes a novel design for an ultra-high-density and high-throughput DNA synthesis platform. The presented design mainly leverages two functional modules: a dynamic random-access memory (DRAM)-like integrated circuit (IC) responsible for electrode addressing and voltage supply, and the static droplet array (SDA)-based microfluidic structure to eliminate any reaction species diffusion concern in electrochemical DNA synthesis. Through theoretical analysis and simulation studies, we validate the effective addressing of 10 million electrodes and stable, adjustable voltage supply by the integrated circuit. We also demonstrate a reaction unit size down to 3.16 × 3.16 µm2, equivalent to 10 million/cm2, that can rapidly and stably generate static droplets at each site, effectively constraining proton diffusion. Finally, we conducted a synthesis cycle experiment by incorporating fluorescent beacons on a microfabricated electrode array to examine the feasibility of our design.

A Solvent Exchange Induced Robust Wet Adhesive Hydrogels to Treat Solid Tumor Through Synchronous Ethanol Ablation and Chemotherapy.

The treatment of tumors in developing countries, especially those with poor medical conditions, remains a significant challenge. Herein, a novel solvent-exchange strategy to prepare adhesive hydrogels for the concurrent treatment of tumors through synchronous ethanol ablation and local chemotherapy is reported. First, a poly (gallic acid-lipoic acid) (PGL) ethanol gel is prepared that can undergo solvent exchange with water to form a hydrogel in situ. PGL ethanol gel deposited on the wet tissue can form a hydrogel in situ to effectively repel interfacial water and establish a tight contact between the hydrogel and tissue. Additionally, the functional groups between the hydrogels and tissues can form covalent and non-covalent bonds, resulting in robust adhesion. Furthermore, this PGL ethanol gel demonstrates exceptional capacity to effectively load antitumor drugs, allowing for controlled and sustained release of the drugs locally and sustainably both in vitro and in vivo. In addition, the PGL ethanol gel can combine ethanol ablation and local chemotherapy to enhance the antitumor efficacy in vitro and in vivo. The PGL ethanol gel-derived hydrogel shows robust wet bioadhesion, drug loading, sustained release, good biocompatibility and biodegradability, easy preparation and usage, and cost-effectiveness, which make it a promising bioadhesive for diverse biomedical applications.

The role of circular RNA during the urological cancer metastasis: exploring regulatory mechanisms and potential therapeutic targets.

Metastasis is a major contributor to treatment failure and death in urological cancers, representing an important biomedical challenge at present. Metastases form as a result of cancer cells leaving the primary site, entering the vasculature and lymphatic vessels, and colonizing clones elsewhere in the body. However, the specific regulatory mechanisms of action underlying the metastatic process of urological cancers remain incompletely elucidated. With the deepening of research, circular RNAs (circRNAs) have been found to not only play a significant role in tumor progression and prognosis but also show aberrant expression in various tumor metastases, consequently impacting tumor metastasis through multiple pathways. Therefore, circRNAs are emerging as potential tumor markers and treatment targets. This review summarizes the research progress on elucidating how circRNAs regulate the urological cancer invasion-metastasis cascade response and related processes, as well as their role in immune microenvironment remodeling and circRNA vaccines. This body of work highlights circRNA regulation as an emerging therapeutic target for urological cancers, which should motivate further specific research in this regard.

A Novel Coacervate Embolic Agent for Tumor Chemoembolization.

Transcatheter arterial chemoembolization (TACE) has proven effective in blocking tumor-supplied arteries and delivering localized chemotherapeutic treatment to combat tumors. However, traditional embolic TACE agents exhibit certain limitations, including insufficient chemotherapeutic drug-loading and sustained-release capabilities, non-biodegradability, susceptibility to aggregation, and unstable mechanical properties. This study introduces a novel approach to address these shortcomings by utilizing a complex coacervate as a liquid embolic agent for tumor chemoembolization. By mixing oppositely charged quaternized chitosan (QCS) and gum arabic (GA), a QCS/GA polymer complex coacervate with shear-thinning property is obtained. Furthermore, the incorporation of the contrast agent Iohexol (I) and the chemotherapeutic doxorubicin (DOX) into the coacervate leads to the development of an X-ray-opaque QCS/GA/I/DOX coacervate embolic agent capable of carrying drugs. This innovative formulation effectively embolizes the renal arteries without recanalization. More importantly, the QCS/GA/I/DOX coacervate can successfully embolize the supplying arteries of the VX2 tumors in rabbit ear and liver. Coacervates can locally release DOX to enhance its therapeutic effects, resulting in excellent antitumor efficacy. This coacervate embolic agent exhibits substantial potential for tumor chemoembolization due to its shear-thinning performance, excellent drug-loading and sustained-release capabilities, good biocompatibility, thrombogenicity, biodegradability, safe and effective embolic performance, and user-friendly application.

Surface functionalized titanium nitride electrode for CMOS compatible bioelectronic devices.

In this study, a surface functionalization approach by covalent grafting of an organic thin film containing hydroxyl groups on TiN surface via electroreduction of diazonium salts "4-(2-hydroxyethyl)benzenediazonium salt" is presented. Cyclic voltammetry procedures were carried out at the potential ranges of -0.8 V~0.5 V (vs Ag/AgCl) with varying numbers of potential cycles (i.e., 5, 25, and 50 cycles) in order to study the thickness of modification layer. Then, the electrochemical properties, surface morphology, and chemical structures of the sample before and after modifications were investigated via multiple characterization techniques, such as cyclic voltammetry (CV), atomic force microscopy (AFM), scanning electron microscope (SEM) and X-ray photoelectron spectroscopy (XPS), etc., thereby confirming the successful grafting of hydroxyl groups onto the TiN surface. The experiments on DNA synthesis aimed to explore the potential of modified TiN electrode as a novel platform for DNA data storage applications and the corresponding proof-of-principle was accomplished by the process of coupling Cy3-phosphoramidite. Finally, the experiments were successfully reproduced on the randomly selected sites of the modified TiN microarray chips demonstrating the potential of technical protocol to extend applications in future bioelectronic devices, such as bio-sensing, high-throughput DNA synthesis, and molecular manipulation.

High biocompatible bone screw enabled by a rapid and robust chitosan/silk fibroin composite material.

Hydrogel has attracted tremendous attentions due to its excellent biocompatibility and adaptability in biomedical field. However, it is challenging by the conflicts between inadequate mechanical properties and service requirements. Herein, a rapid and robust hydrogel was developed by interpenetrating networks between chitosan and silk fibroin macromolecules. Thanks to these unique networks, the chitosan-based hydrogel exhibited superior mechanical performances. The maximum breaking strength, Young's modulus and swelling ratio of the hydrogel were 1187.8 kPa, 383.1 MPa and 4.5 % respectively. The hydrogel also supported the proliferation of human umbilical vein endothelial cells for 7 days. Notably, the hydrogel was easily molded into bone screw, and demonstrated compressive strengths of 45.7 MPa, Young's modulus of 675.6 MPa, respectively. After 49-day biodegradation, the residual rate of the screw in collagenase I solution was up to 89.6 % of the initial weight. In vitro, the screws not only had high resistance to biodegradation, but also had outstanding biocompatibility of osteoblast. This study provided a promising physical-chemical double crosslinking strategy to build orthopedic materials, holding a great potential in biomedical devices.

Molecular Twist-Induced Single-Crystal Isomerization and Valence Tautomeric Transitions in a Cobalt-Dioxolene Complex.

A mononuclear valence tautomeric (VT) complex, [Co(pycz)2(Sq)(Cat)] (1-trans), where pycz = 9-(pyridin-4-yl)-9H-carbazole, Sq⋅- = 3,5-di-tert-butyl-semiquinonato, and Cat2- = 3,5-di-tert-butyl-catecholato, is synthesized in the trans configuration, which undergoes one-step valence tautomeric transition above room temperature. Remarkably, 1-trans can transform into its isomeric structure, [Co(pycz)2(Sq)(Sq)] (1-cis), at temperature above 350 K in a single-crystal-to-single-crystal way by in situ molecular twist, and the resulting 1-cis exhibits a pronounced two-step VT transition during magnetic measurements that is rare for mononuclear VT complexes. Such drastic solid-state structural transformation is reported in VT compounds for the first time, which is actuated by a crystal surface's melting-recrystallization induced phase transition process. DFT calculations offer an underlying mechanism suggesting a concerted bond rotation during the structural transformation. The results demonstrate an unconventional approach that realizes structural transformation of VT complexes and the control of VT performance.

Clinical and Genetic Analysis of Multiple Idiopathic Cervical Root Resorption.

OBJECTIVE: To explore the genetic background and clinical phenotypes of multiple idiopathic cervical root resorption (MICRR) in a Chinese family. METHODS: The proband and his three family members were clinically examined and had radiographs taken with a radiovisiography (RVG) system and CBCT to define the diagnosis of MICRR. Genomic DNA (gDNA) was extracted from peripheral blood samples of the patient, his father, mother and younger sister for whole exome sequencing (WES). The pathogenicity of rare variants with minor allele frequency (MAF) less than 0.005 were analysed following possible inheritance patterns, predicted results from 12 software programs, the American College of Medical Genetics (ACMG) 2015 criteria, and information from ClinVar, OMIM and HGMD databases as well as gene function. RESULTS: The proband presented the typical MICRR phenotypes such as thin cervical pulp wall and apple core-like lesions in radiographs. Following the recessive inheritance pattern, WES analysis identified SHROOM2, SYTL5, MAGED1 and FLNA with a higher chance of causing MICRR. Four genes with compound heterozygous variants and another 27 genes with de novo variants either in autosomal-dominant or autosomal-recessive pattern were also found to have the potential pathogenicity. CONCLUSION: A total of 35 novel potential pathogenic genes were found to be associated with MICRR from a Chinese family through WES. The new genetic background of MICRR may be helpful for clinical and molecular diagnosis.

Improving the Effects of Mulberry Leaves and Neochlorogenic Acid on Glucotoxicity-Induced Hepatic Steatosis in High Fat Diet Treated db/db Mice.

There are many complications of type 2 diabetes mellitus. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are two complications related to the increased lipid accumulation in the liver. Previous studies have shown that mulberry leaf water extract (MLE) has the effect of lowering lipid levels in peripheral blood, inhibiting the expression of fatty acid synthase (FASN) and increasing the activity of liver antioxidant enzymes superoxide dismutase (SOD) and catalase. Our study aimed to investigate the role of MLE and its main component, neochlorogenic acid (nCGA), in reducing serum lipid profiles, decreasing lipid deposition in the liver, and improving steatohepatitis levels. We evaluated the antioxidant activity including glutathione (GSH), glutathione reductase (GRd), glutathione peroxidase (GPx), glutathione S-transferase (GST), and superoxide dismutase (SOD), and catalase was tested in mice fed with MLE and nCGA. The results showed a serum lipid profile, and fatty liver scores were significantly increased in the HFD group compared to the db/m and db mice groups, while liver antioxidant activity significantly decreased in the HFD group. When fed with HFD + MLE or nCGA, there was a significant improvement in serum lipid profiles, liver fatty deposition conditions, steatohepatitis levels, and liver antioxidant activity compared to the HFD group. Although MLE and nCGA do not directly affect the blood sugar level of db/db mice, they do regulate abnormalities in lipid metabolism. These results demonstrate the potential of MLE/nCGA as a treatment against glucotoxicity-induced diabetic fatty liver disease in animal models.

Rational Design of 2D Metal Halide Perovskites with Low Congruent Melting Temperature and Large Melt-Processable Window.

Metal halide perovskites (MHPs) have garnered significant attention due to their distinctive optical and electronic properties, coupled with excellent processability. However, the thermal characteristics of these materials are often overlooked, which can be harnessed to cater to diverse application scenarios. We showcase the efficacy of lowering the congruent melting temperature (Tm) of layered 2D MHPs by employing a strategy that involves the modification of flexible alkylammonium through N-methylation and I-substitution. Structural-property analysis reveals that the N-methylation and I-substitution play pivotal roles in reducing hydrogen bond interactions between the organic components and inorganic parts, lowering the rotational symmetry number of the cation and restricting the residual motion of the cations. Additional I···I interactions enhance intermolecular interactions and lead to improved molten stability, as evidenced by a higher viscosity. The 2D MHPs discussed in this study exhibit low Tm and wide melt-processable windows, e.g., (DMIPA)2PbI4 showcasing a low Tm of 98 °C and large melt-processable window of 145 °C. The efficacy of the strategy was further validated when applied to bromine-substituted 2D MHPs. Lowering the Tm and enhancing the molten stability of the MHPs hold great promise for various applications, including glass formation, preparation of high-quality films for photodetection, and fabrication of flexible devices.

Acyl-CoA synthetase 1 plays an important role on pollen development and male fertility in tomato.

The development of pollen is critical to male reproduction in flowering plants. Acyl-CoA synthetase (ACOS) genes play conserved functions in regulating pollen development in various plants. Our previous work found that knockout of the SlACOS1 gene in tomato might decrease fruit setting. The current study further revealed that SlACOS1 was important to pollen development and male fertility. The SlACOS1 gene was preferentially expressed in the stamen of the flower with the highest expression at the tetrad stage of anther development. Mutation of the SlACOS1 gene by the CRISPR/Cas9-editing system reduced pollen number and viability as well as fruit setting. The tapetum layer exhibited premature degradation and the pollen showed abnormal development appearing irregular, shriveled, or anucleate in Slacos1 mutants at the tetrad stage. The fatty acid metabolism in anthers was significantly impacted by mutation of the SlACOS1 gene. Furthermore, targeted fatty acids profiling using GC-MS found that contents of most fatty acids except C18:1 and C18:2 were reduced. Yeast complementation assay demonstrated that the substrate preferences of SlACOS1 were C16:0 and C18:0 fatty acids. Male fertility of Slacos1 mutant could be slightly restored by applying exogenous palmitic acid, a type of C16:0 fatty acid. Taken together, SlACOS1 played important roles on pollen development and male fertility by regulating the fatty acid metabolism and the development of tapetum and tetrad. Our findings will facilitate unraveling the mechanism of pollen development and male fertility in tomato.

High-throughput DNA synthesis for data storage.

With the explosion of digital world, the dramatically increasing data volume is expected to reach 175 ZB (1 ZB = 1012 GB) in 2025. Storing such huge global data would consume tons of resources. Fortunately, it has been found that the deoxyribonucleic acid (DNA) molecule is the most compact and durable information storage medium in the world so far. Its high coding density and long-term preservation properties make itself one of the best data storage carriers for the future. High-throughput DNA synthesis is a key technology for "DNA data storage", which encodes binary data stream (0/1) into quaternary long DNA sequences consisting of four bases (A/G/C/T). In this review, the workflow of DNA data storage and the basic methods of artificial DNA synthesis technology are outlined first. Then, the technical characteristics of different synthesis methods and the state-of-the-art of representative commercial companies, with a primary focus on silicon chip microarray-based synthesis and novel enzymatic DNA synthesis are presented. Finally, the recent status of DNA storage and new opportunities for future development in the field of high-throughput, large-scale DNA synthesis technology are summarized.

Measuring the quality of transitional care based on elderly patients' experiences with the partners at care transitions measure: a cross-sectional survey.

BACKGROUND: The quality of transitional care is closely related to the health outcomes of patients, and understanding the status of transitional care for patients is crucial to improving the health outcomes of patients. Therefore, this study aims to investigate the quality of transitional care in elderly patients with chronic diseases and analyze its influencing factors, to provide a basis for improving transitional care services. METHODS: This is a cross-sectional study. We used the Chinese version of the Partners at Care Transitions Measure (PACT-M) to survey patients with chronic diseases aged 60 years and older who were about to be discharged from five tertiary hospitals in Henan and Shanxi provinces. We used the mean ± standard deviation to describe the quality of transitional care, t-test or one-way ANOVA, and regression analysis to explore the factors affecting the quality of transitional care for patients. RESULTS: 182 elderly patients with chronic diseases aged ≥ 60 years completed the PACT-M survey. The scores of PACT-M1 and PACT-M2 were (30.69 ± 7.87) and (25.59 ± 7.14) points, respectively. The results of the t-test or one-way ANOVA showed that the patient's marital status, ethnicity, religion, educational level, preretirement occupation, residence, household income per month, and living situation had an impact on the quality of transitional care for elderly patients with chronic diseases (P < 0.05). The results of regression analyses showed that patients' preretirement occupation, social support, and health status were the main influences on the quality of transitional care for elderly patients with chronic diseases (P < 0.05), and they explained 63.1% of the total variance. CONCLUSIONS: The quality of transitional care for older patients with chronic illnesses during the transition from hospital to home needs further improvement. Factors affecting the quality of transitional care included patients' pre-retirement occupation, social support, and health status. We can improve the hospital-community-family tertiary linkage service to provide coordinated and continuous transitional care for patients based on their occupation, health status, and social support to enhance the quality of transitional care and the patient's health.

Quercetin attenuates cisplatin-induced mitochondrial apoptosis via PI3K/Akt mediated inhibition of oxidative stress in pericytes and improves the blood labyrinth barrier permeability.

Cisplatin (CDDP) is broadly employed to treat different cancers, whereas there are no drugs approved by the Food and Drug Administration (FDA) for preventing its side effects, including ototoxicity. Quercetin (QU) is a widely available natural flavonoid compound with anti-tumor and antioxidant properties. The research was designed to explore the protective effects of QU on CDDP-induced ototoxicity and its underlying mechanisms in male C57BL/6 J mice and primary cultured pericytes (PCs). Hearing changes, morphological changes of stria vascularis, blood labyrinth barrier (BLB) permeability and expression of apoptotic proteins were observed in vivo by using the auditory brainstem response (ABR) test, HE staining, Evans blue staining, immunohistochemistry, western blotting, etc. Oxidative stress levels, mitochondrial function and endothelial barrier changes were observed in vitro by using DCFH-DA probe detection, flow cytometry, JC-1 probe, immunofluorescence and the establishment in vitro BLB models, etc. QU pretreatment activates the PI3K/AKT signaling pathway, inhibits CDDP-induced oxidative stress, protects mitochondrial function, and reduces mitochondrial apoptosis in PCs. However, PI3K/AKT specific inhibitor (LY294002) partially reverses the protective effects of QU. In addition, in vitro BLB models were established by coculturing PCs and endothelial cells (ECs), which suggests that QU both reduces the CDDP-induced apoptosis in PCs and improves the endothelial barrier permeability. On the whole, the research findings suggest that QU can be used as a novel treatment to reduce CDDP-induced ototoxicity.

Designing an Air-Stable Interphase on Lithium Metal Anode to Improve Cycling Performance.

The application of rechargeable lithium metal batteries is challenged by intractable issues of uncontrollable Li dendrite growth that result in poor cycle life and safety risks. In this work, an air-stable interphase is developed to protect the lithium metal anode (LMA) via a facile solution-based approach. The Ag-embedded fluoride-rich interphase not only creates abundant lithiophilic sites for homogenizing Li nucleation and growth but also resists severe air erosion to protect the LMA beneath and enable decent cycling stability. As a result, the Ag-F-rich interphase enables flat Li deposition on LMA, which is clearly observed in the operando Li plating experiments. Paired with a LiFePO4 cathode (11.8 mg cm-2), the Ag-F-rich interphase-modified LMA enables 300 stable cycles at 0.5 C, delivering a capacity retention ratio as high as 91.4%. Even after being exposed to air for 1 h, the modified LMA still runs smoothly for over 120 cycles with ignorable capacity decay, exhibiting great air stability. This work proves the concept of functionalizing the interphase on the LMA to enable good cycling performance even under severe air erosion.

Glycogen synthase kinase-3: A potential immunotherapeutic target in tumor microenvironment.

Glycogen synthase kinase-3(GSK-3) is a protein kinase that can phosphorylate over a hundred substrates and regulate cell differentiation, proliferation, and death. Researchers have acknowledged the pivotal role of abnormal activation of GSK-3 in the progression of various diseases over the past few decades. Recent studies have mostly concentrated on investigating the function of GSK-3 in the tumor microenvironment, specifically examining the interaction between TAM, NK cells, B cells, and T cells. Furthermore, GSK-3 exhibits a strong association with immunological checkpoints, such as programmed cell death protein 1. Novel GSK-3 inhibitors have potential in tumor immunotherapy, exerting beneficial effects on hematologic diseases and solid tumors. Nevertheless, there is a lack of reviews about the correlation between tumor-associated immune cells and GSK-3. This study intends to analyze the function and mechanism of GSK-3 comprehensively and systematically in the tumor microenvironment, with a special focus on its influence on various immune cells. The objective is to present novel perspectives for GSK-3 immunotherapy.