Impact of Single Acyclic Phosphonate Nucleotide (ZNA) Modifications on DNA Duplex Stability.

An acyclic phosphonate-linked nucleic acid backbone (ZNA) demonstrated the capability to support duplex formation and propagate genetic information in vivo, unveiling its potential for evolution into a synthetic genetic system (XNA). To determine the structural impact of such modification, modified Dickerson Drew DNA dodecamers (DDDs) were prepared by solid phase synthesis, each containing either an (R) or (S) isomeric form of a cytosine ZNA nucleotide. While the DDD is known to adopt a stable duplex, both duplex and hairpin forms were simultaneously observed for both modified oligonucleotides by NMR spectroscopy over a broad temperature range (5-65 °C). Diffusion-ordered spectroscopy (DOSY) experiments allowed to separate duplex and hairpin signals based on the different diffusion constants of both conformational states. For the oligomer containing (R)-ZNA, only the duplex form occurred at 5 °C, while it was not possible to determine by NMR a single hairpin conformation at higher temperatures. In the case of the (S)-ZNA nucleoside modified oligomer, both hairpin and duplex forms were observable at 0 °C, while a single hairpin conformation was detected at 37 °C, suggesting a higher destabilizing effect on dsDNA.

Mid1 promotes synovitis in rheumatoid arthritis via ubiquitin-dependent post-translational modification.

INTRODUCTION: Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed. OBJECTIVES: To explore the role of Midline-1 (Mid1) in synovial activation. METHODS: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were used to establish a subcutaneous xenograft model. Wild-type C57BL/6, Mid1-/-, Dpp4-/-, and Mid1-/-Dpp4-/- mice were used to establish a collagen-induced arthritis model. Cell viability, cell cycle, qPCR and western blotting analysis were used to detect MH7A proliferation, dipeptidyl peptidase-4 (DPP4) and Mid1 levels. Co-immunoprecipitation and proteomic analysis identified the candidate protein of Mid1 substrates. Ubiquitination assays were used to determine DPP4 ubiquitination status. RESULTS: An increase in Mid1, an E3 ubiquitin ligase, was observed in human RA synovial tissue by GEO dataset analysis, and this elevation was confirmed in a collagen-induced mouse arthritis model. Notably, deletion of Mid1 in a collagen-induced arthritis model completely protected mice from developing arthritis. Subsequent overexpression and knockdown experiments on MH7A, a human synoviocyte cell line, unveiled a previously unrecognized role of Mid1 in synoviocyte proliferation and migration, the key aspects of synovial activation. Co-immunoprecipitation and proteomic analysis identified DPP4 as the most significant candidate of Mid1 substrates. Mechanistically, Mid1 promoted synoviocyte proliferation and migration by inducing ubiquitin-mediated proteasomal degradation of DPP4. DPP4 deficiency led to increased proliferation, migration, and inflammatory cytokine production in MH7A, while reconstitution of DPP4 significantly abolished Mid1-induced augmentation of cell proliferation and activation. Additionally, double knockout model showed that DPP4 deficiency abolished the protective effect of Mid1 defect on arthritis. CONCLUSION: Overall, our findings suggest that the ubiquitination of DPP4 by Mid1 promotes synovial cell proliferation and invasion, exacerbating synovitis in RA. These results reveal a novel mechanism that controls synovial activation, positioning Mid1 as a promising target for therapeutic intervention in RA.

ZrTe2 Compound Dirac Semimetal Contacts for High-Performance MoS2 Transistors.

Recent investigations reveal elemental semimetal (Bi and Sb) contacts fabricated with conventional deposition processes exhibit a remarkable capacity of approaching the quantum limit in two-dimensional (2D) semiconductor contacts, implying it might be an optimal option to solve the contact issue of 2D semiconductor electronics. Here, we demonstrate novel compound Dirac semimetal ZrTe2 contacts to MoS2 constructed by a nondestructive van der Waals (vdW) transfer process, exhibiting excellent ohmic contact characteristics with a negligible Schottky barrier. The band hybridization between ZrTe2 and MoS2 was verified. The bilayer MoS2 transistor with a 250 nm channel length on a 20 nm thick hexagonal boron nitride (h-BN) exhibits an ION/IOFF current ratio over 105 and an on-state current of 259 µA µm-1. The current results reveal that 2D compound semimetals with vdW contacts can offer a diverse selection of proper semimetals with adjustable work functions for the next-generation 2D-based beyond-silicon electronics.

Preparation and application of high-brightness red carbon quantum dots for pH and oxidized L-glutathione dual response.

Carbon dots (CDs) with red fluorescence emission are highly desirable for use in bioimaging and trace- substance detection, with potential applications in biotherapy, photothermal therapy, and tumor visualization. Most CDs emit green or blue fluorescence, thus limiting their applicability. We report a novel fluorescent detection platform based on high-brightness red fluorescence emission carbon dots (R-CDs) co-doped with nitrogen and bromine, which exhibit pH and oxidized L-glutathione (GSSG) dual-responsive characteristics. The absolute quantum yield of the R-CDs was as high as 11.93%. We discovered that the R-CDs were able to detect acidic pH in live cells and zebrafish owing to protonation and deprotonation. In addition, GSSG was detected in vitro over a broad linear range (8-200 µM) using the R-CDs with excitation-independent emission. Furthermore, cell imaging and bioimaging experiments demonstrated that the R-CDs were highly cytocompatible and could be used as fluorescent probes to target lysosomes and nucleolus. These studies highlight the promising prospects of R-CDs as biosensing tools for bioimaging and trace-substance detection applications.

Nitrogen-doped orange emitting carbon dots for ß-carotene detection and lysosomal imaging.

ß-Carotene is a natural antioxidant that has an indispensable effect on the growth and immunity of the human body. For intracellular and in vitro detection of ß-carotene, N-doped carbon quantum dots (O-CDs) were prepared by co-heating carbonization of 1,5-naphthalenediamine and nitric acid in ethanol solvent for 2 h at 200 °C. O-CDs have longer wavelength orange light emission, with an optimal excitation peak of 470 nm and an optimal emission peak of 590 nm. According to the principle of the internal filtering effect on which the detection system is based, O-CDs present a good linear relationship with ß-carotene within a wide range of 0-2000 µM, and the R2 coefficient of the linear regression equation is 0.999. In addition, O-CDs showed targeting of lysosomes in cell imaging and could be used to detect intracellular lysosomal movement. These experiments show that O-CDs can be used for in vivo and in vitro detection of ß-carotene and can serve as a potential substitute to commercial lysosome targeting probes.

An Interactive Framework of Cross-Lingual NLU for In-Vehicle Dialogue.

As globalization accelerates, the linguistic diversity and semantic complexity of in-vehicle communication is increasing. In order to meet the needs of different language speakers, this paper proposes an interactive attention-based contrastive learning framework (IABCL) for the field of in-vehicle dialogue, aiming to effectively enhance cross-lingual natural language understanding (NLU). The proposed framework aims to address the challenges of cross-lingual interaction in in-vehicle dialogue systems and provide an effective solution. IABCL is based on a contrastive learning and attention mechanism. First, contrastive learning is applied in the encoder stage. Positive and negative samples are used to allow the model to learn different linguistic expressions of similar meanings. Its main role is to improve the cross-lingual learning ability of the model. Second, the attention mechanism is applied in the decoder stage. By articulating slots and intents with each other, it allows the model to learn the relationship between the two, thus improving the ability of natural language understanding in languages of the same language family. In addition, this paper constructed a multilingual in-vehicle dialogue (MIvD) dataset for experimental evaluation to demonstrate the effectiveness and accuracy of the IABCL framework in cross-lingual dialogue. With the framework studied in this paper, IABCL improves by 2.42% in intent, 1.43% in slot, and 2.67% in overall when compared with the latest model.

Tunneling Magnetoresistance in Noncollinear Antiferromagnetic Tunnel Junctions.

Antiferromagnetic (AFM) spintronics has emerged as a subfield of spintronics driven by the advantages of antiferromagnets producing no stray fields and exhibiting ultrafast magnetization dynamics. The efficient method to detect an AFM order parameter, known as the Néel vector, by electric means is critical to realize concepts of AFM spintronics. Here, we demonstrate that noncollinear AFM metals, such as Mn_{3}Sn, exhibit a momentum dependent spin polarization which can be exploited in AFM tunnel junctions to detect the Néel vector. Using first-principles calculations, we predict a tunneling magnetoresistance (TMR) effect as high as 300% in AFM tunnel junctions with Mn_{3}Sn electrodes, where the junction resistance depends on the relative orientation of their Néel vectors and exhibits four nonvolatile resistance states. We argue that the spin-split band structure and the related TMR effect can also be realized in other noncollinear AFM metals like Mn_{3}Ge, Mn_{3}Ga, Mn_{3}Pt, and Mn_{3}GaN. Our work provides a robust method for detecting the Néel vector in noncollinear antiferromagnets via the TMR effect, which may be useful for their application in AFM spintronic devices.

Van der Waals Multiferroic Tunnel Junctions.

Multiferroic tunnel junctions (MFTJs) have aroused significant interest due to their functional properties useful for nonvolatile memory devices. So far, however, all of the existing MFTJs have been based on perovskite-oxide heterostructures limited by a relatively high resistance-area (RA) product unfavorable for practical applications. Here, using first-principles calculations, we explore spin-dependent transport properties of van der Waals (vdW) MFTJs which consist of two-dimensional (2D) ferromagnetic FenGeTe2 (n = 3, 4, 5) electrodes and 2D ferroelectric In2Se3 barrier layers. We demonstrate that such FemGeTe2/In2Se3/FenGeTe2 (m, n = 3, 4, 5; m ≠ n) MFTJs exhibit multiple nonvolatile resistance states associated with different polarization orientation of the ferroelectric In2Se3 layer and magnetization alignment of the two ferromagnetic FenGeTe2 layers. We find a remarkably low RA product (less than 1 Ω·µm2) which makes the proposed vdW MFTJs superior to the conventional MFTJs in terms of their promise for nonvolatile memory applications.

Mechanism and kinetics characteristic of self-discharge of FeS2 cathodes for thermal batteries.

The service life of FeS2 thermal batteries is significantly affected by self-discharge of the cathode. Herein, SEM, XRD and XPS were employed to characterize the mechanism of self-discharge of the FeS2 cathode. A novel combined-discharge method, in which a tiny current (5 mA cm-2) was applied to minimize the effect of polarization on discharge capacity, was conducted to study the kinetics characteristic of self-discharge of FeS2 cathode upon discharge. Then, the self-discharge kinetics parameters which are related to the current density (20, 50 and 200 mA cm-2) and temperature (400, 450, 500 and 550 °C) were determined by the Serin-Ellickson model. Characterizations of the cells standing at 500 °C confirm that the decomposition product of the FeS2 cathode is FeS. The quantitative analysis of self-discharge rate constants (SRC) demonstrates that the reaction is a diffusion-controlling process. The kinetics process can conform to the Serin-Ellickson model. Specifically, the values of SRC increase when the cell is carried by a heavier load, since more breakage would form in FeS2 particles at the larger current density. Besides, the SRC increase at a higher temperature, and the relationship of SRC and temperature can be fitted by the Arrhenius equation. Consequently, the apparent activation energy decreases with the increase of current density.

Laboratory Predictors of COVID-19 Mortality: A Retrospective Analysis from Tongji Hospital in Wuhan.

BACKGROUND: Novel coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly progressed to a global pandemic. Currently, there are limited effective medications approved for this deadly disease. OBJECTIVE: To investigate the potential predictors of COVID-19 mortality and risk factors for hyperinflammation in COVID-19. METHODS: Retrospective analysis was carried out in 1,149 patients diagnosed with COVID-19 in Tongji Hospital, Wuhan, China, from 1/13/2020 to 3/15/2020. RESULTS: We found significant differences in the rates of hyperuricemia (OR: 3.17, 95% CI: 2.13-4.70; p < 0.001) and hypoalbuminemia (OR: 5.68, 95% CI: 3.97-8.32; p < 0.001) between deceased and recovered patients. The percentages of hyperuricemia in deceased patients and recovered patients were 23.6% and 8.9%, respectively, which were higher than the reported age-standardized prevalence of 6.2% in Chinese population. Of note, the percentages of both IL-6 and uric acid levels in survived COVID-19 patients were above 90%, suggesting that they might be good specificity for indicators of mortality in COVID-19 patients. The serum level of uric acid (UA) was positively associated with ferritin, TNF-α, and IL-6 but not with anti-inflammatory cytokine IL-10. In addition, the levels of these proinflammatory cytokines in COVID-19 patients showed a trend of reduction after uric acid lowering therapy. CONCLUSIONS: Our results suggest that uric acid, the end product of purine metabolism, was increased in deceased patients with COVID-19. In addition, the serum level of uric acid was positively associated with inflammatory markers. Uric acid lowering therapy in COVID-19 patients with hyperuricemia may be beneficial.

Extraction, Radical Scavenging Activities, and Chemical Composition Identification of Flavonoids from Sunflower (Helianthus annuus L.) Receptacles.

This study was focused on extraction, radical scavenging activities, and chemical composition identification of total flavonoids in sunflower (Helianthus annuus L.) receptacles (TFSR). We investigated the optimal extract parameters of TFSR using response surface methodology. The highest yield of TFSR was 1.04% with the ethanol concentration 58%, the material-to-liquid ratio 1:20 (v/w), the extraction time 2.6 h, and the extraction temperature 67 °C. The results of radical scavenging activities showed that ethyl acetate fraction (EAF) was the strongest by using 2-diphenyl-1-picrylhydrazyl (DPPH), 2, 2'-azino-bis (3-ethylbenzo thiazoline-6-sulfonic acid) (ABTS) and iron ion reducing analysis. The EAF had the highest flavonoids contents. Four fractions A, B, C and D were enrichment from EAF by polyamide resin. Fraction B had the highest flavonoids content. Thirteen chemical components of flavonoids in fraction B were first identified by Ultimate 3000 Nano LC System coupled to a Q Exactive HF benchtop Orbitrap mass spectrometer (UHPLC-HRMS/MS). Among of the thirteen chemical components, isoquercetin and daidzein were identified accurately by comparing with standard samples. Radical scavenging analysis showed that isoquercetin and EAF had strong activities. Therefore, sunflower receptacles can be used as a source of natural flavonoids. TFSR as a natural radical scavenger has potential applications in pharmaceutical industry.

Spin-Dependent Transport in van der Waals Magnetic Tunnel Junctions with Fe3GeTe2 Electrodes.

van der Waals (vdW) heterostructures, stacking different two-dimensional materials, have opened up unprecedented opportunities to explore new physics and device concepts. Especially interesting are recently discovered two-dimensional magnetic vdW materials, providing new paradigms for spintronic applications. Here, using density functional theory (DFT) calculations, we investigate the spin-dependent electronic transport across vdW magnetic tunnel junctions (MTJs) composed of Fe3GeTe2 ferromagnetic electrodes and a graphene or hexagonal boron nitride (h-BN) spacer layer. For both types of junctions, we find that the junction resistance changes by thousands of percent when the magnetization of the electrodes is switched from parallel to antiparallel. Such a giant tunneling magnetoresistance (TMR) effect is driven by dissimilar electronic structure of the two spin-conducting channels in Fe3GeTe2, resulting in a mismatch between the incoming and outgoing Bloch states in the electrodes and thus suppressed transmission for an antiparallel-aligned MTJ. The vdW bonding between electrodes and a spacer layer makes this result virtually independent of the type of the spacer layer, making the predicted giant TMR effect robust with respect to strain, interface distance, and other parameters, which may vary in the experiment. We hope that our results will further stimulate experimental studies of vdW MTJs and pave the way for their applications in spintronics.

Chemical Composition and Antimicrobial and Antioxidant Activities of Essential Oil of Sunflower (Helianthus annuus L.) Receptacle.

Sunflower (Helianthus annuus L.) contains active ingredients, such as flavonoids, alkaloids and tannins. Nevertheless, few studies have focused on essential oil from the receptacle of sunflower (SEO). In this work, we investigated the chemical composition and antimicrobial and antioxidant activities of SEO. The yield of SEO was about 0.42% (v/w) by hydrodistillation. A total of 68 volatile components of SEO were putatively identified by gas chromatography-mass spectrometry (GC-MS). The main constituents of SEO were α-pinene (26.00%), verbenone (7.40%), terpinolene (1.69%) and α-terpineol (1.27%). The minimum inhibitory concentration (MIC) of SEO against P. aeruginosa and S. aureus was 0.2 mg/mL. The MIC of SEO against S. cerevisiae was 3.2 mg/mL. The MIC of SEO against E. coli and Candida albicans was 6.4 mg/mL. The results showed that SEO had high antibacterial and antifungal activities. Three different analytical assays (DPPH, ABTS and iron ion reducing ability) were used to determine the antioxidant activities. The results showed that SEO had antioxidant activities. To summarize, the results in this study demonstrate the possibility for the development and application of SEO in potential natural preservatives and medicines due to its excellent antimicrobial and antioxidant activities.

Structures of ubiquitin-like (Ubl) and Hsp90-like domains of sacsin provide insight into pathological mutations.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease that is caused by mutations in the SACS gene. The product of this gene is a very large 520-kDa cytoplasmic protein, sacsin, with a ubiquitin-like (Ubl) domain at the N terminus followed by three large sacsin internal repeat (SIRPT) supradomains and C-terminal J and HEPN domains. The SIRPTs are predicted to contain Hsp90-like domains, suggesting a potential chaperone activity. In this work, we report the structures of the Hsp90-like Sr1 domain of SIRPT1 and the N-terminal Ubl domain determined at 1.55- and 2.1-Å resolutions, respectively. The Ubl domain crystallized as a swapped dimer that could be relevant in the context of full-length protein. The Sr1 domain displays the Bergerat protein fold with a characteristic nucleotide-binding pocket, although it binds nucleotides with very low affinity. The Sr1 structure reveals that ARSACS-causing missense mutations (R272H, R272C, and T201K) disrupt protein folding, most likely leading to sacsin degradation. This work lends structural support to the view of sacsin as a molecular chaperone and provides a framework for future studies of this protein.

3D-QSAR based optimization of insect neuropeptide allatostatin analogs.

Allatostatins (AST) are neuropeptides originally described as inhibitors of juvenile hormone (JH) synthesis in insects. Consequently, they have been considered as potential lead compounds for the discovery of new insect growth regulators (IGRs). In the present work, receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) was studied with 48 AST analogs, and a general approach for novel potent bioactive AST analogs is proposed. Hence, six novel AST analogs were designed and synthesized. Bioassays indicated that the majority novel analogs exhibited potent JH inhibitory activity, especially analog A6 (IC50: 3.79 nmol/L), which can be used as lead compound to develop new IGRs.

Energy Efficient Hybrid Routing Protocol Based on the Artificial Fish Swarm Algorithm and Ant Colony Optimisation for WSNs.

Wireless Sensor Networks (WSNs) are a particular type of distributed self-managed network with limited energy supply and communication ability. The most significant challenge of a routing protocol is the energy consumption and the extension of the network lifetime. Many energy-efficient routing algorithms were inspired by the development of Ant Colony Optimisation (ACO). However, due to the inborn defects, ACO-based routing algorithms have a slow convergence behaviour and are prone to premature, stagnation phenomenon, which hinders further route discovery, especially in a large-scale network. This paper proposes a hybrid routing algorithm by combining the Artificial Fish Swarm Algorithm (AFSA) and ACO to address these issues. We utilise AFSA to perform the initial route discovery in order to find feasible routes quickly. In the route discovery algorithm, we present a hybrid algorithm by combining the crowd factor in AFSA and the pseudo-random route select strategy in ACO. Furthermore, this paper presents an improved pheromone update method by considering energy levels and path length. Simulation results demonstrate that the proposed algorithm avoids the routing algorithm falling into local optimisation and stagnation, whilst speeding up the routing convergence, which is more prominent in a large-scale network. Furthermore, simulation evaluation reports that the proposed algorithm exhibits a significant improvement in terms of network lifetime.

Structural studies of parkin and sacsin: Mitochondrial dynamics in neurodegenerative diseases.

Neurodegenerative diseases are prevalent, chronic diseases emanating from the dysfunction or death of neurons. The disrupted mitochondrial dynamics observed in a large number of neurodegenerative diseases suggests a common etiology with the possibility of therapies targeting multiple diseases. This review highlights the contributions of structural studies of disease-related proteins to the understanding of neurodegenerative disease pathogenesis and especially the cellular events leading to disruptions in mitochondrial dynamics and function. The examples used are parkin and sacsin, two proteins linked respectively to autosomal-recessive early-onset PD and autosomal-recessive spastic ataxia of Charlevoix-Saguenay. Structural studies of parkin and sacsin explain the pathogenicity of a large number of disease-associated mutations and reveal insights into their cellular functions related to mitochondrial dynamics.

Dental pulp regeneration strategies: A review of status quo and recent advances.

Microorganisms, physical factors such as temperature or mechanical injury, and chemical factors such as free monomers from composite resin are the main causes of dental pulp diseases. Current clinical treatment methods for pulp diseases include the root canal therapy, vital pulp therapy and regenerative endodontic therapy. Regenerative endodontic therapy serves the purpose of inducing the regeneration of new functional pulp tissues through autologous revascularization or pulp tissue engineering. This article first discusses the current clinical methods and reviews strategies as well as the research outcomes regarding the pulp regeneration. Then the in vivo models, the prospects and challenges for regenerative endodontic therapy were further discussed.

Novel Zn0.079V2O5·0.53H2O/Graphene aerogel as high-rate and long-life cathode materials of aqueous zinc-ion batteries.

Aqueous zinc-ion batteries (ZIBs) have attracted more and more attention due to their advantages of low cost, high safety and environmental protection. Unfortunately, the unsatisfactory capacity at high current density and long-term cycling performance of cathode materials hinder the development of ZIBs. Here, a novel Zn0.079V2O5·0.53H2O/graphene (ZVOH@rGO) hybrid aerogel composed of ultrathin Zn0.079V2O5·0.53H2O (ZVOH) nanoribbons and 3D continuous graphene conductive network was successfully prepared and used as cathode of ZIBs. Taking advantage of the synergistic effects associated with ion doping, morphology control and unique aerogel structure, the ZVOH@rGO electrode demonstrated ultrafast charge/discharge capability and remarkable cycling stability: A high reversible capacity of 286.7 mAh g-1 was achieved at a current density as large as 30 A g-1, and an impressive capacity retention ratio of 75.6 % was realized over 9800 ultra-long cycles at 12 A g-1. This work is of great significance for the synthesis modification of vanadium oxides and the development of high performance ultrafast charge-discharge ZIBs.

Upstream nitrogen availability determines the Microcystis salt tolerance and influences microcystins release in brackish water.

The occurrence of large Microcystis biomass in brackish waters is primarily caused by its downward transportation from the upstream freshwater lakes and reservoirs through rivers rather than due to in situ bloom formation. Factors that determine the survival of freshwater cyanobacteria in brackish waters have not been well investigated. Here, we studied the spatiotemporal variability of inorganic nitrogen in an upstream lake and conducted laboratory and in-situ experiments to assess the role of nitrogen availability on the salt tolerance of Microcystis and the release of microcystins. A series of field experiments were carried out during bloom seasons to evaluate the salt tolerance of natural Microcystis colonies. The salt tolerance threshold varied from 7 to 17 and showed a positive relationship with intracellular carbohydrate content and a negative relationship with nitrogen availability in water. In August when upstream nitrogen availability was lower, the Microcystis colonies could maintain their biomass even after a sudden increase in salinity from 4 to 10. Laboratory-cultivated Microcystis that accumulated higher carbohydrate content at lower nitrogen availability showed better cell survival at higher salinity. The sharp release of microcystins into the surrounding water occurred when salinity exceeded the salt tolerance threshold of the Microcystis. Thus, Microcystis with higher salt tolerance can accumulate more toxins in cells. The obtained results suggest that the cell survival and toxin concentration in brackish waters depend on the physiological properties of Microcystis formed in the upstream waters. Thus, the life history of Microcystis in upstream waters could have a significant impact on its salt tolerance in downstream brackish waters, where the ecological risk of the salt-tolerant Microcystis requires special and careful management in summer at low nitrogen availability.