Prevention and treatment of HPV-related cancer through a mRNA vaccine expressing APC-targeting antigen.

Persistent human papillomavirus (HPV) infection is associated with multiple malignancies. Developing therapeutic vaccines to eliminate HPV-infected and malignant cells holds significant value. In this study, we introduced a lipid nanoparticle encapsulated mRNA vaccine expressing tHA-mE7-mE6. Mutations were introduced into E6 and E7 of HPV to eliminate their tumourigenicity. A truncated influenza haemagglutinin protein (tHA), which binds to the CD209 receptor on the surface of dendritic cells (DCs), was fused with mE7-mE6 in order to allow efficient uptake of antigen by antigen presenting cells. The tHA-mE7-mE6 (mRNA) showed higher therapeutic efficacy than mE7-mE6 (mRNA) in an E6 and E7+ tumour model. The treatment resulted in complete tumour regression and prevented tumour formation. Strong CD8+ T-cell immune response was induced, contributing to preventing and curing of E6 and E7+ tumour. Antigen-specific CD8+ T were found in spleens, peripheral blood and in tumours. In addition, the tumour infiltration of DC and NK cells were increased post therapy. In conclusion, this study described a therapeutic mRNA vaccine inducing strong anti-tumour immunity in peripheral and in tumour microenvironment, holding promising potential to treat HPV-induced cancer and to prevent cancer recurrence.

Microplastics supply contaminants in food chain: non-negligible threat to health safety.

The occurrence of microplastics (MPs) and organic pollutants (OPs) residues is commonly observed in diverse environmental settings, where their interactions can potentially alter the behavior, availability, and toxicity of OPs, thereby posing risks to ecosystems. Herein, we particularly emphasize the potential for bioaccumulation and the biomagnification effect of MPs in the presence of OPs within the food chain. Despite the ongoing influx of novel information, there exists a dearth of data concerning the destiny and consequences of MPs in the context of food pollution. Further endeavors are imperative to unravel the destiny and repercussions of MPs/OPs within food ecosystems and processing procedures, aiming to gain a deeper understanding of the joint effect on human health and food quality. Nevertheless, the adsorption and desorption behavior of coexisting pollutants can be significantly influenced by MPs forming biofilms within real-world environments, including temperature, pH, and food constituents. A considerable portion of MPs tend to accumulate in the epidermis of vegetables and fruits, thus necessitating further research to comprehend the potential ramifications of MPs on the infiltration behavior of OPs on agricultural product surfaces.

Studies on the Synergistic Effect of Tandem Semi-Stable Complementary Domains on Sequence-Defined DNA Block Copolymers.

Tandem semi-stable complementary domains play an important role in life, while the role of these domains in the folding process of nucleic acid molecules has not been systematically studied. Here, we designed a clean model system by synthesizing sequence-defined DNA-OEG copolymers composed of ssDNA fragments with palindromic sequences and orthogonal oligo(tetraethylene glycol) (OEG) linkers. By altering the lengths of DNA units (6-12 nt) and OEG linkers (Xn = 0-4) separately, we systematically studied how stabilities of tandem complementary domains and connecting flexibilities affect the assembly topology. Combining experimental methods and coarse-grained molecular simulation analysis, distributions of multiple assembled conformations (mainly monomers, dimers, and clusters) were characterized. Both results indicated that tandem semi-stable complementary domains tend to form homogeneous closed circular dimers instead of larger clusters due to the synergistic enhancement effect, and the distributions of each conformation highly depend on flexibilities.

Phosphate Polymer Nanogel for Selective and Efficient Rare Earth Element Recovery.

Demand for rare earth elements (REEs) is increasing, and REE production from ores is energy-intensive. Recovering REEs from waste streams can provide a more sustainable approach to help meet REE demand but requires materials with high selectivity and capacity for REEs due to the low concentration of REEs and high competing ion concentrations. Here, we developed a phosphate polymer nanogel (PPN) to selectively recover REEs from low REE content waste streams, including leached fly ash. A high phosphorus content (16.2 wt % P as phosphate groups) in the PPN provides an abundance of coordination sites for REE binding. In model solutions, the distribution coefficient (Kd) for all REEs ranged from 1.3 × 105 to 3.1 × 105 mL g-1 at pH = 7, and the sorption capacity (qm) for Nd, Gd, and Ho were ∼300 mg g-1. The PPN was selective toward REEs, outcompeting cations (Ca, Mg, Fe, Al) at up to 1000-fold excess concentration. The PPN had a Kd of ∼105-106 mL g-1 for lanthanides in coal fly ash leachate (pH = 5), orders of magnitude higher than the Kd of major competing ions (∼103-104 mL g-1). REEs were recovered from the PPN using 3.5% HNO3, and the material remained effective over three sorption-elution cycles. The high REE capacity and selectivity and good durability in a real waste stream matrix suggest its potential to recover REEs from a broad range of secondary REE stocks.

Amphiphilic Thiol Polymer Nanogel Removes Environmentally Relevant Mercury Species from Both Produced Water and Hydrocarbons.

Technologies for removal of mercury from produced water and hydrocarbon phases are desired by oil and gas production facilities, oil refineries, and petrochemical plants. Herein, we synthesize and demonstrate the efficacy of an amphiphilic, thiol-abundant (11.8 wt % S, as thiol) polymer nanogel that can remove environmentally relevant mercury species from both produced water and the liquid hydrocarbon. The nanogel disperses in both aqueous and hydrocarbon phases. It has a high sorption affinity for dissolved Hg(II) complexes and Hg-dissolved organic matter complexes found in produced water and elemental (Hg0) and soluble Hg-alkyl thiol species found in hydrocarbons. X-ray absorption spectroscopy analysis indicates that the sorbed mercury is transformed to a surface-bound Hg(SR)2 species in both water and hydrocarbon regardless of its initial speciation. The nanogel had high affinity to native mercury species present in real produced water (>99.5% removal) and in natural gas condensate (>85% removal) samples, removing majority of the mercury species using only a 50 mg L-1 applied dose. This thiolated amphiphilic polymeric nanogel has significant potential to remove environmentally relevant mercury species from both water and hydrocarbon at low applied doses, outperforming reported sorbents like sulfur-impregnated activated carbons because of the mass of accessible thiol groups in the nanogel.

Kinetically Interlocking Multiple-Units Polymerization of DNA Double Crossover and Its Application in Hydrogel Formation.

A novel kinetically interlocking multiple-units (KIMU) supramolecular polymerization system with DNA double crossover backbone is designed. The rigidity of DX endows the polymer with high molecular weight and stability. The observed concentration of the formed polymers is insensitive and stable under ultralow monomer concentration owing to the KIMU interactions, in which multiple noncovalent interactions are connected by the phosphodiester bonds. Furthermore, a pH-responsive DNA supramolecular hydrogel is constructed by introducing a half i-motif domain into the DNA monomer. The rigidity of DNA polymer endows the hydrogel with high mechanical strength and low gelation concentration. This study enriches the KIMU strategy and offers a simple but effective way to fabricate long and stable supramolecular polymers by balancing the reversibility and stability. It also shows great potentials to construct next generation of smart materials, such as DNA nanostructures, DNA motors, and DNA hydrogels.

Supramolecular Polymeric Radicals: Highly Promoted Formation and Stabilization of Naphthalenediimide Radical Anions.

The supramolecular polymeric radicals are developed to promote the generation efficiency and stability of naphthalenediimide (NDI) radical anions. To this end, a water-soluble bifunctional monomer bearing two naphthalene-viologen end groups and a NDI center is designed and synthesized. The supramolecular polymeric NDI radical anions are fabricated on the basis of host-guest complexation between the NDI-containing bifunctional monomer and cucurbit[8]uril (CB[8]) and followed by the photoinduced electron transfer process under UV light irradiation. The electrostatic effect of CB[8] and the bulky and rigid structure of supramolecular polymer are combined to stabilize the excited state of NDIs and NDI radical anions, contributing to the high enhancement of the formation of NDI radical anions with excellent stability. It is found that the highest occupied molecular orbital energy and lowest unoccupied molecular orbital energy of NDI are also lowered by the formation of supramolecular polymer. In addition, the supramolecular polymeric NDI radical anions could be utilized as a supramolecular photoreducing agent to reduce cytochrome C with a higher efficiency. It is anticipated that other radicals can also be stabilized through this strategy, and this line of research may lead to the development of novel polymeric radical materials.

Research on Temperature Variation during Coal and Gas Outbursts: Implications for Outburst Prediction in Coal Mines.

Coal and gas outbursts are among the most severe disasters threatening the safety of coal mines around the world. They are dynamic phenomena characterized by large quantities of coal and gas ejected from working faces within a short time. Numerous researchers have conducted studies on outburst prediction, and a variety of indices have been developed to this end. However, these indices are usually empirical or based on local experience, and the accurate prediction of outbursts is not feasible due to the complicated mechanisms of outbursts. This study conducts outburst experiments using large-scale multifunctional equipment developed in the laboratory to develop a more robust outburst prediction method. In this study, the coal temperature during the outburst process was monitored using temperature sensors. The results show that the coal temperature decreased rapidly as the outburst progressed. Meanwhile, the coal temperature in locations far from the outburst mouth increased. The coal broken in the stress concentration state is the main factor causing the abnormal temperature rise. The discovery of these phenomena lays a theoretical foundation and provides an experimental basis for an effective outburst prediction method. An outburst prediction method based on monitoring temperature was proposed, and has a simpler and faster operation process and is not easily disturbed by coal mining activities. What is more, the critical values of coal temperature rises or temperature gradients can be flexibly adjusted according to the actual situations of different coal mines to predict outbursts more effectively and accurately.

Spilanthol Enhances Sensitivity to Sodium in Mouse Taste Bud Cells.

Overconsumption of NaCl has been linked to increased hypertension-related morbidity. Compounds that can enhance NaCl responses in taste cells could help reduce human NaCl consumption without sacrificing perceived saltiness. Spilanthol is an unsaturated alkylamide isolated from the Jambu plant (Acmella oleracea) that can induce tingling, pungency, and numbing in the mouth. Structurally similar fatty acid amides, such as sanshool, elicit numbing and tingling sensations by inhibiting 2-pore-domain potassium leak channels on trigeminal sensory neurons. Even when insufficient to induce action potential firing, leak current inhibition causes depolarization and increased membrane resistance, which combine to make cells more sensitive to subsequent depolarizing stimuli, such as NaCl. Using calcium imaging, we tested whether spilanthol alters sensitivity to NaCl in isolated circumvallate taste bud cells and trigeminal sensory neurons of mice (Mus musculus). Micromolar spilanthol elicited little to no response in taste bud cells or trigeminal neurons. These same perithreshold concentrations of spilanthol significantly enhanced responses to NaCl (140 and 200 mM) in taste bud cells. Trigeminal neurons, however, exhibited response enhancement only at the highest concentrations of NaCl and spilanthol tested. Using a combination of potassium depolarization, immunohistochemistry, and Trpm5-GFP and Tas1r3-GFP mice to characterize taste bud cells by type, we found spilanthol enhancement of NaCl responses most prevalent in NaCl-responsive type III cells, and commonly observed in NaCl-responsive type II cells. Our results indicate that spilanthol enhances NaCl responses in taste bud cells and point to a family of compounds that may have utility as salty taste enhancers.

Fibrin-Targeted Polymerized Shell Microbubbles as Potential Theranostic Agents for Surgical Adhesions.

The development of new therapies for surgical adhesions has proven to be difficult as there is no consistently effective way to assess treatment efficacy in clinical trials without performing a second surgery, which can result in additional adhesions. We have developed lipid microbubble formulations that use a short peptide sequence, CREKA, to target fibrin, the molecule that forms nascent adhesions. These targeted polymerized shell microbubbles (PSMs) are designed to allow ultrasound imaging of early adhesions for diagnostic purposes and for evaluating the success of potential treatments in clinical trials while acting as a possible treatment. In this study, we show that CREKA-targeted microbubbles preferentially bind fibrin over fibrinogen and are stable for long periods of time (∼48 h), that these bound microbubbles can be visualized by ultrasound, and that neither these lipid-based bubbles nor their diagnostic-ultrasound-induced vibrations damage mesothelial cells in vitro. Moreover, these bubbles show the potential to identify adhesionlike fibrin formations and may hold promise in blocking or breaking up fibrin formations in vivo.

Clinical value of Naa10p and CEA levels in saliva and serum for diagnosis of oral squamous cell carcinoma.

BACKGROUND: N-α-acetyltransferase 10 protein (Naa10p) is a potential prognostic biomarker that modulates the phenotypes of several cancer types. Carcinoembryonic antigen (CEA) is currently the most well-known biomarker for the detection of epithelial malignancies. Our objective was to evaluate the clinical value of Naa10p, CEA, and their combined detection for diagnosis of oral squamous cell carcinoma (OSCC). METHODS: This study included 202 individuals: 112 patients with OSCC, 30 patients with oral premalignant lesions (OPMLs), and 60 cancer-free and without OPML patients as control. Naa10p and CEA were determined in serum and saliva samples utilizing enzyme-linked immunosorbent assays. RESULTS: Salivary and serum levels of Naa10p and CEA in OSCC patients were significantly higher than those detected in OPML and the control groups, although patients with OPMLs also showed increased salivary and serum Naa10p and CEA levels as compared to the control group. Salivary Naa10p level in OSCC patients is correlated with the degree of differentiation and lymph node metastasis, and serum Naa10p level is specifically correlated with patient age. Additionally, salivary CEA level is correlated with the clinical stage and lymph node metastasis, whereas serum CEA level is correlated with lymph node metastasis. The sensitivity, specificity, positive predictive value, and negative predictive value of combined detection were greater than any single detection. CONCLUSIONS: Combined use of salivary Naa10p and CEA as tumor markers for OSCC was more sensitive than serum Naa10p and CEA. These results indicated that combined detection of salivary Naa10p and CEA improved diagnostic performance and early detection rate for OSCC.

Heterochromatin remodeling by CDK12 contributes to learning in Drosophila.

Dynamic regulation of chromatin structure is required to modulate the transcription of genes in eukaryotes. However, the factors that contribute to the plasticity of heterochromatin structure are elusive. Here, we report that cyclin-dependent kinase 12 (CDK12), a transcription elongation-associated RNA polymerase II (RNAPII) kinase, antagonizes heterochromatin enrichment in Drosophila chromosomes. Notably, loss of CDK12 induces the ectopic accumulation of heterochromatin protein 1 (HP1) on euchromatic arms, with a prominent enrichment on the X chromosome. Furthermore, ChIP and sequencing analysis reveals that the heterochromatin enrichment on the X chromosome mainly occurs within long genes involved in neuronal functions. Consequently, heterochromatin enrichment reduces the transcription of neuronal genes in the adult brain and results in a defect in Drosophila courtship learning. Taken together, these results define a previously unidentified role of CDK12 in controlling the epigenetic transition between euchromatin and heterochromatin and suggest a chromatin regulatory mechanism in neuronal behaviors.

Supramolecular Polymerization from Controllable Fabrication to Living Polymerization.

Supramolecular polymers have attracted plenty of interest in the scientific community; however, developing controllable methods of supramolecular polymerization remains a serious challenge. This article reviews some recent developments of methods for supramolecular polymerization from controllable fabrication to living polymerization. Three facile methods with general applicability for controllable fabrication of supramolecular polymers have been established recently: the first method is a self-sorting approach by manipulating ring-chain equilibrium based on noncovalent control over rigidity of monomers; the second is covalent polymerization from supramonomers formed by noncovalent interactions; and the third is supramolecular interfacial polymerization. More excitingly, living supramolecular polymerization has been achieved by two elegant strategies, including seeded supramolecular polymerization under pathway complexity control and chain-growth supramolecular polymerization by metastable monomers. It is anticipated that this review may provide some guidance for precise fabrication of supramolecular polymers, leading to the construction of supramolecular polymeric materials with controllable architectures and functions.

Photoinduced transformations of stiff-stilbene-based discrete metallacycles to metallosupramolecular polymers.

Control over structural transformations in supramolecular entities by external stimuli is critical for the development of adaptable and functional soft materials. Herein, we have designed and synthesized a dipyridyl donor containing a central Z-configured stiff-stilbene unit that self-assembles in the presence of two 180° di-Pt(II) acceptors to produce size-controllable discrete organoplatinum(II) metallacycles with high efficiency by means of the directional-bonding approach. These discrete metallacycles undergo transformation into extended metallosupramolecular polymers upon the conformational switching of the dipyridyl ligand from Z-configured (0°) to E-configured (180°) when photoirradiated. This transformation is accompanied by interesting morphological changes at nanoscopic length scales. The discrete metallacycles aggregate to spherical nanoparticles that evolve into long nanofibers upon polymer formation. These fibers can be reversibly converted to cyclic oligomers by changing the wavelength of irradiation, which reintroduces Z-configured building blocks owing to the reversible nature of stiff-stilbene photoisomerization. The design strategy defined here represents a novel self-assembly pathway to deliver advanced supramolecular assemblies by means of photocontrol.

Morphology, composition, and bioactivity of strontium-doped brushite coatings deposited on titanium implants via electrochemical deposition.

Surface modification techniques have been applied to generate titanium implant surfaces that promote osseointegration for use in dental applications. In this study, strontium-doped brushite coatings were deposited on titanium by electrochemical deposition. The phase composition of the coating was investigated by energy dispersive X-ray spectroscopy and X-ray diffraction. The surface morphologies of the coatings were studied through scanning electron microscopy, and the cytocompatibility and bioactivity of the strontium-doped brushite coatings were evaluated using cultured osteoblasts. Osteoblast proliferation was enhanced by the addition of strontium, suggesting a possible mechanism by which strontium incorporation in brushite coatings increased bone formation surrounding the implants. Cell growth was also strongly influenced by the composition of the deposited coatings, with a 10% Sr-doped brushite coating inducing the greatest amount of bone formation among the tested materials.

The effects of nanoplastics and microcystin-LR coexposure on Aristichthys nobilis at the early developmental stages.

Nanoplastics (NPs) and microcystin-LR (MC-LR) are two common and harmful pollutants in water environments, especially at aquafarm where are full of plastic products and algae. It is of great significance to study the toxic effects and mechanisms of the NPs and/or MC-LR on fish at the early stage. In this study, the embryo and larvae of a filtering-feeding fish, Aristichthys nobilis, were used as the research objects. The results showed that the survival and hatching rates of the embryo were not significantly affected by the environmental concentration exposure of these two pollutants. Scanning electron microscopy (SEM) observation displayed that NPs adhered to the surface of the embryo membrane. Transcriptomic and bioinformatic analyses revealed that the NPs exposure activated neuromuscular junction development and skeletal muscle fiber in larvae, and affected C5-Branched dibasic acid metabolism. The metabolic and biosynthetic processes of zeaxanthin, xanthophyll, tetraterpenoid, and carotenoid were suppressed after the MC-LR exposure, which was harmful to the retinol metabolism of fish. Excessive production of superoxide dismutase (SOD) was detected under the MC-LR exposure. The MC-LR and NPs coexposure triggered primary immunodeficiency and adaptive immune response, leading to the possibility of reduced fitness of A.nobilis during the development. Collectively, our results indicate that environmental concentration NPs and MC-LR coexposure could cause toxic damage and enhance sick risk in A.nobilis, providing new insights into the risk of NPs and MC-LR on filtering-feeding fish.

Genomic insight into domestication of rubber tree.

Understanding the genetic basis of rubber tree (Hevea brasiliensis) domestication is crucial for further improving natural rubber production to meet its increasing demand worldwide. Here we provide a high-quality H. brasiliensis genome assembly (1.58 Gb, contig N50 of 11.21 megabases), present a map of genome variations by resequencing 335 accessions and reveal domestication-related molecular signals and a major domestication trait, the higher number of laticifer rings. We further show that HbPSK5, encoding the small-peptide hormone phytosulfokine (PSK), is a key domestication gene and closely correlated with the major domestication trait. The transcriptional activation of HbPSK5 by myelocytomatosis (MYC) members links PSK signaling to jasmonates in regulating the laticifer differentiation in rubber tree. Heterologous overexpression of HbPSK5 in Russian dandelion (Taraxacum kok-saghyz) can increase rubber content by promoting laticifer formation. Our results provide an insight into target genes for improving rubber tree and accelerating the domestication of other rubber-producing plants.

Optimisation of a Mouse Model of Cerebral Ischemia-Reperfusion to Address Issues of Survival and Model Reproducibility and Consistency.

Middle cerebral artery occlusion (MCAO) induced brain ischemia-reperfusion model in Mice is essential for understanding the pathology of stroke and investigating potential treatments, in which a variety of methods may be employed to block the middle cerebral artery (MCA), the most common being through the insertion of a monofilament; however, in vivo ischemia-reperfusion models are associated, particularly in mice, with high variability in lesion volume and high mortality. We aimed to optimise a mouse model of cerebral ischemia-reperfusion, addressing issues of mouse survival, model reproducibility, and consistency. The model was optimised in two ways: first, insert the monofilament directly through the internal carotid artery rather than through the external or common carotid artery, and second, by extending the length of the silicone coating on the monofilament, the length of the silicone coating enables embolization of the beginning of the middle cerebral artery, as well as the anterior cerebral artery and part of the posterior communicating artery. Results: We assessed various parameters, including blood flow changes in the middle cerebral artery, stability of the infarct area, correlation between infarct volume percentages and neurological deficit scores, mortality, weight changes, and wellbeing. We found that optimisation of the surgical procedure may improve mouse wellbeing and reduce mortality, through reduced weight loss and decrease the variability. In conclusion, we suggest that the optimisation of the model is superior for the study of both short and long-term outcomes of ischemic stroke. These results have considerable implications on stroke model selection for researchers.

Closed-loop chemical recycling of cross-linked polymeric materials based on reversible amidation chemistry.

Closed-loop chemical recycling provides a solution to the end-of-use problem of synthetic polymers. However, it remains a major challenge to design dynamic bonds, capable of effective bonding and reversible cleaving, for preparing chemically recyclable cross-linked polymers. Herein, we report a dynamic maleic acid tertiary amide bond based upon reversible amidation reaction between maleic anhydrides and secondary amines. This dynamic bond allows for the construction of polymer networks with tailorable and robust mechanical properties, covering strong elastomers with a tensile strength of 22.3 MPa and rigid plastics with a yield strength of 38.3 MPa. Impressively, these robust polymeric materials can be completely depolymerized in an acidic aqueous solution at ambient temperature, leading to efficient monomer recovery with >94% separation yields. Meanwhile, the recovered monomers can be used to remanufacture cross-linked polymeric materials without losing their original mechanical performance. This work unveils a general approach to design polymer networks with tunable mechanical performance and closed-loop recyclability, which will open a new avenue for sustainable polymeric materials.

Triton X-100 improves the reactivity and selectivity of sulfidized nanoscale zerovalent iron toward tetrabromobisphenol A: Implications for groundwater and soil remediation.

Sulfidized nanoscale zerovalent iron (SNZVI) with improved reactivity and selectivity has shown great potential for environmental remediation. However, it is unclear if SNZVI could be applied for the remediation of soil washing solution, and how a soil-washing surfactant affects the reactivity and selectivity of SNZVI. Here, we assess the impact of Triton X-100 (TX-100) on the reactivity and selectivity of a sulfidized commercial NZVI toward tetrabromobisphenol A (TBBPA). While sulfidation of NZVI improved its reactivity and electron efficiency toward TBBPA, TX-100 could further improve these promoting effects, which was 8-21 and 4-7 times higher than those without TX-100, respectively, depending on TX-100 concentration. Because TX-100 could induce the solubilization of TBBPA, sorb onto the SNZVI surface, and favor the subsequent sorption and degradation of TBBPA. SNZVI performance for successive treatments of TBBPA contaminated water was also greatly improved by TX-100. Moreover, washing the TBBPA-contaminated soil with TX-100 could efficiently extract the TBBPA, and almost all of the TBBPA in the soil washing solution could be efficiently degraded by SNZVI. These results suggest that TX-100 is a good additive to SNZVI for improving its performance, and SNZVI coupled with TX-100 can be a promising technology for the remediation of TBBPA-contaminated soil.