RNA aggregates harness the danger response for potent cancer immunotherapy.

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

A universal interface for plug-and-play assembly of stretchable devices.

Stretchable hybrid devices have enabled high-fidelity implantable1-3 and on-skin4-6 monitoring of physiological signals. These devices typically contain soft modules that match the mechanical requirements in humans7,8 and soft robots9,10, rigid modules containing Si-based microelectronics11,12 and protective encapsulation modules13,14. To make such a system mechanically compliant, the interconnects between the modules need to tolerate stress concentration that may limit their stretching and ultimately cause debonding failure15-17. Here, we report a universal interface that can reliably connect soft, rigid and encapsulation modules together to form robust and highly stretchable devices in a plug-and-play manner. The interface, consisting of interpenetrating polymer and metal nanostructures, connects modules by simply pressing without using pastes. Its formation is depicted by a biphasic network growth model. Soft-soft modules joined by this interface achieved 600% and 180% mechanical and electrical stretchability, respectively. Soft and rigid modules can also be electrically connected using the above interface. Encapsulation on soft modules with this interface is strongly adhesive with an interfacial toughness of 0.24 N mm-1. As a proof of concept, we use this interface to assemble stretchable devices for in vivo neuromodulation and on-skin electromyography, with high signal quality and mechanical resistance. We expect such a plug-and-play interface to simplify and accelerate the development of on-skin and implantable stretchable devices.

Water-responsive supercontractile polymer films for bioelectronic interfaces.

Connecting different electronic devices is usually straightforward because they have paired, standardized interfaces, in which the shapes and sizes match each other perfectly. Tissue-electronics interfaces, however, cannot be standardized, because tissues are soft1-3 and have arbitrary shapes and sizes4-6. Shape-adaptive wrapping and covering around irregularly sized and shaped objects have been achieved using heat-shrink films because they can contract largely and rapidly when heated7. However, these materials are unsuitable for biological applications because they are usually much harder than tissues and contract at temperatures higher than 90 °C (refs. 8,9). Therefore, it is challenging to prepare stimuli-responsive films with large and rapid contractions for which the stimuli and mechanical properties are compatible with vulnerable tissues and electronic integration processes. Here, inspired by spider silk10-12, we designed water-responsive supercontractile polymer films composed of poly(ethylene oxide) and poly(ethylene glycol)-α-cyclodextrin inclusion complex, which are initially dry, flexible and stable under ambient conditions, contract by more than 50% of their original length within seconds (about 30% per second) after wetting and become soft (about 100 kPa) and stretchable (around 600%) hydrogel thin films thereafter. This supercontraction is attributed to the aligned microporous hierarchical structures of the films, which also facilitate electronic integration. We used this film to fabricate shape-adaptive electrode arrays that simplify the implantation procedure through supercontraction and conformally wrap around nerves, muscles and hearts of different sizes when wetted for in vivo nerve stimulation and electrophysiological signal recording. This study demonstrates that this water-responsive material can play an important part in shaping the next-generation tissue-electronics interfaces as well as broadening the biomedical application of shape-adaptive materials.

Genomic and structural basis for evolution of tropane alkaloid biosynthesis.

The tropane alkaloids (TAs) cocaine and hyoscyamine have been used medicinally for thousands of years. To understand the evolutionary origins and trajectories of serial biosynthetic enzymes of TAs and especially the characteristic tropane skeletons, we generated the chromosome-level genome assemblies of cocaine-producing Erythroxylum novogranatense (Erythroxylaceae, rosids clade) and hyoscyamine-producing Anisodus acutangulus (Solanaceae, asterids clade). Comparative genomic and phylogenetic analysis suggested that the lack of spermidine synthase/N-methyltransferase (EnSPMT1) in ancestral asterids species contributed to the divergence of polyamine (spermidine or putrescine) methylation in cocaine and hyoscyamine biosynthesis. Molecular docking analysis and key site mutation experiments suggested that ecgonone synthases CYP81AN15 and CYP82M3 adopt different active-site architectures to biosynthesize the same product ecgonone from the same substrate in Erythroxylaceae and Solanaceae. Further synteny analysis showed different evolutionary origins and trajectories of CYP81AN15 and CYP82M3, particularly the emergence of CYP81AN15 through the neofunctionalization of ancient tandem duplication genes. The combination of structural biology and comparative genomic analysis revealed that ecgonone methyltransferase, which is responsible for the biosynthesis of characteristic 2-substituted carboxymethyl group in cocaine, evolved from the tandem copies of salicylic acid methyltransferase by the mutations of critical E216 and S153 residues. Overall, we provided strong evidence for the independent origins of serial TA biosynthetic enzymes on the genomic and structural level, underlying the chemotypic convergence of TAs in phylogenetically distant species.

Genomic and transcriptomic significance of multiple primary lung cancers detected by next-generation sequencing in clinical settings.

Effective diagnosis and understanding of the mechanism of intrapulmonary metastasis (IM) from multiple primary lung cancers (MPLC) aid clinical management. However, the actual detection panels used in the clinic are variable. Current research on tumor microenvironment (TME) of MPLC and IM is insufficient. Therefore, additional investigation into the differential diagnosis and discrepancies in TME between two conditions is crucial. Two hundred and fourteen non-small cell lung cancer patients with multiple tumors were enrolled and 507 samples were subjected to DNA sequencing (NGS 10). Then, DNA and RNA sequencing (master panel) were performed on the specimens from 32 patients, the TME profiles between tumors within each patient and across patients and the differentially expressed genes were compared. Four patients were regrouped with NGS 10 results. Master panel resolved the classifications of six undetermined patients. The TME in MPLC exhibited a high degree of infiltration by natural killer (NK) cells, CD56dim NK cells, endothelial cells, etc., P < 0.05. Conversely, B cells, activated B cells, regulatory cells, immature dendritic cells, etc., P < 0.001, were heavily infiltrated in the IM. NECTIN4 and LILRB4 mRNA were downregulated in the MPLC (P < 0.0001). Additionally, NECTIN4 (P < 0.05) and LILRB4 were linked to improved disease-free survival in the MPLC. In conclusion, IM is screened from MPLC by pathology joint NGS 10 detections, followed by a large NGS panel for indistinguishable patients. A superior prognosis of MPLC may be associated with an immune-activating TME and the downregulation of NECTIN4 and LILRB4 considered as potential drug therapeutic targets.

Inhibiting collective cation migration in Li-rich cathode materials as a strategy to mitigate voltage hysteresis.

Lithium-rich cathodes are promising energy storage materials due to their high energy densities. However, voltage hysteresis, which is generally associated with transition metal migration, limits their energy efficiency and implementation in practical devices. Here we reveal that voltage hysteresis is related to the collective migration of metal ions, and that isolating the migration events from each other by creating partial disorder can create high-capacity reversible cathode materials, even when migrating transition metal ions are present. We demonstrate this on a layered Li-rich chromium manganese oxide that in its fully ordered state displays a substantial voltage hysteresis (>2.5 V) associated with collective transition metal migration into Li layers, but can be made to achieve high capacity (>360 mAh g-1) and energy density (>1,100 Wh kg-1) when the collective migration is perturbed by partial disorder. This study demonstrates that partially cation-disordered cathode materials can accommodate a high level of transition metal migration, which broadens our options for redox couples to those of mobile cations.

Global prediction for mpox epidemic.

The mpox epidemic had spread worldwide and become an epidemic of international concern. Before the emergence of targeted vaccines and specific drugs, it is necessary to numerically simulate and predict the epidemic. In order to better understand and grasp its transmission situation, and take some countermeasures accordingly when necessary, we predicted and simulated mpox transmission, vaccination and control scenarios using model developed for COVID-19 predictions. The results show that the prediction model can also achieve good results in predicting the mpox epidemic based on modified SEIR model. The total number of people infected with mpox on Dec 31, 2022 reached 83878, while the prediction of the model was 96456 with a relative error of 15%. The United States, Brazil, Spain, France, the United Kingdom and Germany are six countries with serve mpox epidemic. The predictions of their epidemic are 30543, 11191, 7447, 5945, 5606 and 4291 cases respectively, with an average relative error of 20%. If 30% of the population is vaccinated using a vaccine that is 78% effective, the number of infected people will drop by 29%. This shows that the system can be practically applied to the prediction of mpox epidemic and provide corresponding decision-making reference.

Smart osteoclasts targeted nanomedicine based on amorphous CaCO3 for effective osteoporosis reversal.

BACKGROUND: Osteoporosis is characterized by an imbalance in bone homeostasis, resulting in the excessive dissolution of bone minerals due to the acidified microenvironment mediated by overactive osteoclasts. Oroxylin A (ORO), a natural flavonoid, has shown potential in reversing osteoporosis by inhibiting osteoclast-mediated bone resorption. The limited water solubility and lack of targeting specificity hinder the effective accumulation of Oroxylin A within the pathological environment of osteoporosis. RESULTS: Osteoclasts' microenvironment-responsive nanoparticles are prepared by incorporating Oroxylin A with amorphous calcium carbonate (ACC) and coated with glutamic acid hexapeptide-modified phospholipids, aiming at reinforcing the drug delivery efficiency as well as therapeutic effect. The obtained smart nanoparticles, coined as OAPLG, could instantly neutralize acid and release Oroxylin A in the extracellular microenvironment of osteoclasts. The combination of Oroxylin A and ACC synergistically inhibits osteoclast formation and activity, leading to a significant reversal of systemic bone loss in the ovariectomized mice model. CONCLUSION: The work highlights an intelligent nanoplatform based on ACC for spatiotemporally controlled release of lipophilic drugs, and illustrates prominent therapeutic promise against osteoporosis.

Reducing sweetness expectation in milk tea by crossmodal visuo-auditory interaction.

In the realm of healthy dietary choices about reducing sweetness perception, the exploration of crossmodal effects stands as a frequently employed approach. Both music and color can independently influence flavor evaluation and gustatory experience by eliciting emotions. However, less research has been done on the effects of audio-visual crossmodal interactions on sweetness expectations and perceptions. The present study conducted two experiments delving into the crossmodal effect on sweetness expectation and perception of milk tea by manipulating the emotional valence of music and packaging color. The results showed that positive (vs. negative) music led to higher sweetness expectations and perceptions for milk teas with neutral packaging color. Irrespective of music, participants had higher sweetness expectations for milk tea with positive or neutral (vs. negative) packaging colors. The congruence of valence between music and packaging color influenced sweetness perception. Positive (vs. negative) music correlated with a sweeter perception when the packaging color was positive. Exposed to negative music, subjects showed a higher sweetness perception with negative (vs. positive) packaging colors. In conclusion, the results suggest that the valence of music and packaging color crossmodally influence consumers' evaluation of milk tea, and it differs depending on whether it was tasted. Thus, this study has demonstrated the crossmodal influence of music and packaging color, providing valuable implications for healthy eating and marketing applications.

Identification and characterization of camptothecin tailoring enzymes in Nothapodytes tomentosa.

Camptothecin is a complex monoterpenoid indole alkaloid with remarkable antitumor activity. Given that two C-10 modified camptothecin derivatives, topotecan and irinotecan, have been approved as potent anticancer agents, there is a critical need for methods to access other aromatic ring-functionalized congeners (e.g., C-9, C-10, etc.). However, contemporary methods for chemical oxidation are generally harsh and low-yielding when applied to the camptothecin scaffold, thereby limiting the development of modified derivatives. Reported herein, we have identified four tailoring enzymes responsible for C-9 modifications of camptothecin from Nothapodytes tomentosa, via metabolomic and transcriptomic analysis. These consist of a cytochrome P450 (NtCPT9H) which catalyzes the regioselective oxidation of camptothecin to 9-hydroxycamptothecin, as well as two methyltransferases (NtOMT1/2, converting 9-hydroxycamptothecin to 9-methoxycamptothecin), and a uridine diphosphate-glycosyltransferase (NtUGT5, decorating 9-hydroxycamptothecin to 9-ß-D-glucosyloxycamptothecin). Importantly, the critical residues that contribute to the specific catalytic activity of NtCPT9H have been elucidated through molecular docking and mutagenesis experiments. This work provides a genetic basis for producing camptothecin derivatives through metabolic engineering. This will hasten the discovery of novel C-9 modified camptothecin derivatives, with profound implications for pharmaceutical manufacture.

"Urban Respiration" Revealed by Atmospheric O2 Measurements in an Industrial Metropolis.

Urban regions, which "inhale" O2 from the air and "exhale" CO2 and atmospheric pollutants, including harmful gases and fine particles, are the largest sinks of atmospheric O2, yet long-term O2 measurements in urban regions are currently lacking. In this study, we report continuous measurements of atmospheric O2 in downtown Lanzhou, an industrial metropolis in northwestern China. We found declines in atmospheric O2 associated with deteriorated air quality and robust anticorrelations between O2 and gaseous oxides. By combining O2 and pollutants measurements with a Lagrangian atmospheric transport model, we quantitatively break down "urban respiration" (ΔO2URB) into human respiration (ΔO2RES) and fossil fuel combustion (ΔO2FF). We found increased ΔO2FF contribution (from 66.92% to 72.50%) and decreased ΔO2RES contribution (from 33.08 to 27.50%) as O2 declines and pollutants accumulate. Further attribution of ΔO2FF reveals intracity transport of atmospheric pollutants from industrial sectors and suggests transportation sectors as the major O2 sink in downtown Lanzhou. The varying relationships between O2 and pollutants under different conditions unfold the dynamics of urban respiration and provide insights into the O2 and energy consumption, pollutant emission, and intracity atmospheric transport processes.

Desert Abiotic Carbon Sequestration Weakening by Precipitation.

Desert carbon sequestration plays an active role in promoting carbon neutralization. However, the current understanding of the effect of hydrothermal interactions and soil properties on desert carbon sequestration after precipitation remains unclear. Based on the experiment in the hinterland of the Taklimakan Desert, we found that the heavy precipitation will accelerate the weakening of abiotic carbon sequestration in deserts under the background of global warming and intensified water cycle. The high soil moisture can significantly stimulate sand to release CO2 at an incredible speed by rapidly increasing microbial activity and organic matter diffusion. At this time, the CO2 flux in the shifting sand was synergistically affected by soil temperature and soil moisture. As far as soil properties are concerned, with less organic carbon substrate and stronger soil alkalinity, the carbon sequestration of shifting sand is gradually highlighted and strengthened at low temperature. On the contrary, the carbon sequestration of shifting sand is gradually weakened. Our study provides a new way to assess the contribution of desert to the global carbon cycle and improve the accuracy and scope of application.

O-Alkylazoxymycins A-F, Naturally Occurring Azoxy-Aromatic Compounds from Streptomyces sp. Py50.

Six new azoxy-aromatic compounds (o-alkylazoxymycins A-F, 1-6) and two new nitrogen-bearing phenylvaleric/phenylheptanoic acid derivatives (o-alkylphemycins A and B, 7 and 8) were isolated from Streptomyces sp. Py50. Their structures were elucidated based on HRESIMS, NMR, UV spectroscopic analyses, and X-ray crystallographic data. O-Alkylazoxymycins A-F (1-6) are the first natural examples of azoxy compounds with the azoxy bond attached to the ortho-position of the phenylheptanoic acid or phenylvaleric acid moiety. Compounds 1, 5, and 6 were active against Epidermophyton floccosum with MIC50 values ranging from 10.1 to 51.2 µM. A plausible biosynthetic pathway of 2 and 3 was proposed.

Heat waves accelerate the spread of infectious diseases.

COVID-19 pandemic appeared summer surge in 2022 worldwide and this contradicts its seasonal fluctuations. Even as high temperature and intense ultraviolet radiation can inhibit viral activity, the number of new cases worldwide has increased to >78% in only 1 month since the summer of 2022 under unchanged virus mutation influence and control policies. Using the attribution analysis based on the theoretical infectious diseases model simulation, we found the mechanism of the severe COVID-19 outbreak in the summer of 2022 and identified the amplification effect of heat wave events on its magnitude. The results suggest that approximately 69.3% of COVID-19 cases this summer could have been avoided if there is no heat waves. The collision between the pandemic and the heatwave is not an accident. Climate change is leading to more frequent extreme climate events and an increasing number of infectious diseases, posing an urgent threat to human health and life. Therefore, public health authorities must quickly develop coordinated management plans to deal with the simultaneous occurrence of extreme climate events and infectious diseases.

Phytochemical Analysis of Nothapodytes tomentosa and Distribution and Content of Camptothecin and its Analogues in Four Plants.

Camptothecin (CPT) and its derivatives have attracted worldwide attention because of their notable anticancer activity. However, the growing demand for CPT in the global pharmaceutical industry has caused a severe shortage of CPT-producing plant resources. In this study, phytochemical analysis of Nothapodytes tomentosa results in the isolation and identification of CPT (13: ) and 16 analogues (1:  - 12, 14:  - 17: ), including a new (1: ) and five known (9, 10, 12, 15: , and 17: ) CPT analogues with an open E-ring. In view of the potential anticancer activity of CPT analogues with an open E-ring, the fragmentation pathways and mass spectra profiles of these six CPT analogues (1, 9, 10, 12, 15: , and 17: ) are investigated, providing a reference for the rapid detection of these compounds in other plants. Furthermore, based on the fragmentation patterns of CPT (13: ) and known analogues (2:  - 8, 11, 14, 16, 18:  - 26: ), the distribution and content of these compounds in different tissues of N. tomentosa, N. nimmoniana, Camptotheca acuminata, and Ophiorrhiza japonica are further studied. Our findings not only provide an alternative plant resource for further expanding the development and utilization of CPT and its analogues, but also lay a foundation for improving the utilization of known CPT-producing plant resources.

Emotional symptoms, dietary patterns and dental caries: A cross-sectional study in adolescents.

OBJECTIVES: This study investigates the relationship between emotional symptoms and dental caries in adolescents and the role of dietary patterns as mediating variables. METHODS: This cross-sectional study used a multistage stratified random sample of schools, in Jiangsu, with a sample of 17,997 adolescents aged 11-19. Measures included emotional symptoms, dental caries, toothbrushing frequency, and dietary patterns. Logistic and Poisson regression models were conducted to test mediation hypotheses. RESULTS: The decayed, missing, and filled teeth index (DMFT) was related to depressive symptoms following adjustment for other variables (incidence rate ratios [IRR] = 1.09; p < 0.05), but not to anxiety symptoms level (IRR = 1.02; p > 0.05). The link between depressive symptoms and DMFT had a partial mediation impact on toothbrushing frequency (a, b, c' all p < 0.05). Sugary foods, but not fried foods, partially mediated the link between depressive symptoms and caries when toothbrushing frequency was adjusted. CONCLUSION: There are direct and indirect associations between emotional symptoms and caries; the latter may be due to changes in oral health behaviours that increase the risk of caries.

A Federated Learning Multi-Task Scheduling Mechanism Based on Trusted Computing Sandbox.

At present, some studies have combined federated learning with blockchain, so that participants can conduct federated learning tasks under decentralized conditions, sharing and aggregating model parameters. However, these schemes do not take into account the trusted supervision of federated learning and the case of malicious node attacks. This paper introduces the concept of a trusted computing sandbox to solve this problem. A federated learning multi-task scheduling mechanism based on a trusted computing sandbox is designed and a decentralized trusted computing sandbox composed of computing resources provided by each participant is constructed as a state channel. The training process of the model is carried out in the channel and the malicious behavior is supervised by the smart contract, ensuring the data privacy of the participant node and the reliability of the calculation during the training process. In addition, considering the resource heterogeneity of participant nodes, the deep reinforcement learning method was used in this paper to solve the resource scheduling optimization problem in the process of constructing the state channel. The proposed algorithm aims to minimize the completion time of the system and improve the efficiency of the system while meeting the requirements of tasks on service quality as much as possible. Experimental results show that the proposed algorithm has better performance than the traditional heuristic algorithm and meta-heuristic algorithm.

Granule formation mechanism, key influencing factors, and resource recycling in aerobic granular sludge (AGS) wastewater treatment: A review.

The high-efficiency and additionally economic benefits generated from aerobic granular sludge (AGS) wastewater treatment have led to its increasing popularity among academics and industrial players. The AGS process can recycle high value-added biomaterials including extracellular polymeric substances (EPS), sodium alginate-like external polymer (ALE), polyhydroxyfatty acid (PHA), and phosphorus (P), etc., which can serve various fields including agriculture, construction, and chemical while removing pollutants from wastewaters. The effects of various key operation parameters on formation and structural stability of AGS are comprehensively summarized. The degradable metabolism of typical pollutants and corresponding microbial diversity and succession in the AGS wastewater treatment system are also discussed, especially with a focus on emerging contaminants removal. In addition, recent attempts for potentially effective production of high value-added biomaterials from AGS are proposed, particularly concerning improving the yield, quality, and application of these biomaterials. This review aims to provide a reference for in-depth research on the AGS process, suggesting a new alternative for wastewater treatment recycling.

Discovery and Engineering of the Cocaine Biosynthetic Pathway.

Cocaine, the archetypal tropane alkaloid from the plant genus Erythroxylum, has recently been used clinically as a topical anesthesia of the mucous membranes. Despite this, the key biosynthetic step of the requisite tropane skeleton (methylecgonone) from the identified intermediate 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid (MPOA) has remained, until this point, unknown. Herein, we identify two missing enzymes (EnCYP81AN15 and EnMT4) necessary for the biosynthesis of the tropane skeleton in cocaine by transient expression of the candidate genes in Nicotiana benthamiana. Cytochrome P450 EnCYP81AN15 was observed to selectively mediate the oxidative cyclization of S-MPOA to yield the unstable intermediate ecgonone, which was then methylated to form optically active methylecgonone by methyltransferase EnMT4 in Erythroxylum novogranatense. The establishment of this pathway corrects the long-standing (but incorrect) biosynthetic hypothesis of MPOA methylation first and oxidative cyclization second. Notably, the de novo reconstruction of cocaine was realized in N. benthamiana with the two newly identified genes, as well as four already known ones. This study not only reports a near-complete biosynthetic pathway of cocaine and provides new insights into the metabolic networks of tropane alkaloids (cocaine and hyoscyamine) in plants but also enables the heterologous synthesis of tropane alkaloids in other (micro)organisms, entailing significant implications for pharmaceutical production.

Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma.

Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast-cycling cells (FCCs) that have impaired mitochondrial function and rely on aerobic glycolysis. Here, we characterize the metabolic landscape of glioblastoma (GBM) and explore metabolic specificities as targetable vulnerabilities. Our studies highlight the metabolic heterogeneity in GBM, in which FCCs harness aerobic glycolysis, and slow-cycling cells (SCCs) preferentially utilize mitochondrial oxidative phosphorylation for their functions. SCCs display enhanced invasion and chemoresistance, suggesting their important role in tumor recurrence. SCCs also demonstrate increased lipid contents that are specifically metabolized under glucose-deprived conditions. Fatty acid transport in SCCs is targetable by pharmacological inhibition or genomic deletion of FABP7, both of which sensitize SCCs to metabolic stress. Furthermore, FABP7 inhibition, whether alone or in combination with glycolysis inhibition, leads to overall increased survival. Our studies reveal the existence of GBM cell subpopulations with distinct metabolic requirements and suggest that FABP7 is central to lipid metabolism in SCCs and that targeting FABP7-related metabolic pathways is a viable therapeutic strategy.