Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion.

The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program.

Self-assembling dendrimer nanosystems for specific fluorine magnetic resonance imaging and effective theranostic treatment of tumors.

Fluorine magnetic resonance imaging (19F-MRI) is particularly promising for biomedical applications owing to the absence of fluorine in most biological systems. However, its use has been limited by the lack of safe and water-soluble imaging agents with high fluorine contents and suitable relaxation properties. We report innovative 19F-MRI agents based on supramolecular dendrimers self-assembled by an amphiphilic dendrimer composed of a hydrophobic alkyl chain and a hydrophilic dendron. Specifically, this amphiphilic dendrimer bears multiple negatively charged terminals with high fluorine content, which effectively prevented intra- and intermolecular aggregation of fluorinated entities via electrostatic repulsion. This permitted high fluorine nuclei mobility alongside good water solubility with favorable relaxation properties for use in 19F-MRI. Importantly, the self-assembling 19F-MRI agent was able to encapsulate the near-infrared fluorescence (NIRF) agent DiR and the anticancer drug paclitaxel for multimodal 19F-MRI and NIRF imaging of and theranostics for pancreatic cancer, a deadly disease for which there remains no adequate early detection method or efficacious treatment. The 19F-MRI and multimodal 19F-MRI and NIRF imaging studies on human pancreatic cancer xenografts in mice confirmed the capability of both imaging modalities to specifically image the tumors and demonstrated the efficacy of the theranostic agent in cancer treatment, largely outperforming the clinical anticancer drug paclitaxel. Consequently, these dendrimer nanosystems constitute promising 19F-MRI agents for effective cancer management. This study offers a broad avenue to the construction of 19F-MRI agents and theranostics, exploiting self-assembling supramolecular dendrimer chemistry.

The water lily genome and the early evolution of flowering plants.

Water lilies belong to the angiosperm order Nymphaeales. Amborellales, Nymphaeales and Austrobaileyales together form the so-called ANA-grade of angiosperms, which are extant representatives of lineages that diverged the earliest from the lineage leading to the extant mesangiosperms1-3. Here we report the 409-megabase genome sequence of the blue-petal water lily (Nymphaea colorata). Our phylogenomic analyses support Amborellales and Nymphaeales as successive sister lineages to all other extant angiosperms. The N. colorata genome and 19 other water lily transcriptomes reveal a Nymphaealean whole-genome duplication event, which is shared by Nymphaeaceae and possibly Cabombaceae. Among the genes retained from this whole-genome duplication are homologues of genes that regulate flowering transition and flower development. The broad expression of homologues of floral ABCE genes in N. colorata might support a similarly broadly active ancestral ABCE model of floral organ determination in early angiosperms. Water lilies have evolved attractive floral scents and colours, which are features shared with mesangiosperms, and we identified their putative biosynthetic genes in N. colorata. The chemical compounds and biosynthetic genes behind floral scents suggest that they have evolved in parallel to those in mesangiosperms. Because of its unique phylogenetic position, the N. colorata genome sheds light on the early evolution of angiosperms.

Dendrimer nanosystems for adaptive tumor-assisted drug delivery via extracellular vesicle hijacking.

Drug delivery systems (DDSs) that can overcome tumor heterogeneity and achieve deep tumor penetration are challenging to develop yet in high demand for cancer treatment. We report here a DDS based on self-assembling dendrimer nanomicelles for effective and deep tumor penetration via in situ tumor-secreted extracellular vesicles (EVs), an endogenous transport system that evolves with tumor microenvironment. Upon arrival at a tumor, these dendrimer nanomicelles had their payload repackaged by the cells into EVs, which were further transported and internalized by other cells for delivery "in relay." Using pancreatic and colorectal cancer-derived 2D, 3D, and xenograft models, we demonstrated that the in situ-generated EVs mediated intercellular delivery, propagating cargo from cell to cell and deep within the tumor. Our study provides a new perspective on exploiting the intrinsic features of tumors alongside dendrimer supramolecular chemistry to develop smart and effective DDSs to overcome tumor heterogeneity and their evolutive nature thereby improving cancer therapy.

Large and Pressure-Dependent c-Axis Piezoresistivity of Highly Oriented Pyrolytic Graphite near Zero Pressure.

The c-axis piezoresistivity is a fundamental and important parameter of graphite, but its value near zero pressure has not been well determined. Herein, a new method for studying the c-axis piezoresistivity of van der Waals materials near zero pressure is developed on the basis of in situ scanning electron microscopy and finite element simulation. The c-axis piezoresistivity of microscale highly oriented pyrolytic graphite (HOPG) is found to show a large value of 5.68 × 10-5 kPa-1 near zero pressure and decreases by 2 orders of magnitude to the established value of ∼10-7 kPa-1 when the pressure increases to 200 MPa. By modulating the serial tunneling barrier model on the basis of the stacking faults, we describe the c-axis electrical transport of HOPG under compression. The large c-axis piezoresistivity near zero pressure and its large decrease in magnitude with pressure are attributed to the rapid stiffening of the electromechanical properties under compression.

Rational Design of Tetrahedral Derivatives as Efficient Light-Emitting Materials Based on "Super Atom" Perspective.

Traditional semiconductor quantum dots of groups II-VI are key ingredients of next-generation display technology. Yet, the majority of them contain toxic heavy-metal elements, thus calling for alternative light-emitting materials. Herein, we have explored three novel categories of multicomponent compounds, namely, tetragonal II-III2-VI4 porous ternary compounds, cubic I2-II3-VI4 ternary compounds, and cubic I-II-III3-V4 quaternary compounds. This is achieved by judicious introduction of a "super atom" perspective and concurrently varying the solid-state lattice packing of involved super atoms or the population of surrounding counter cations. Based on first-principles calculations of 392 candidate materials with designed crystal structures, 53 highly stable materials have been screened. Strikingly, 34 of them are direct-bandgap semiconductors with emitting wavelengths covering the near-infrared and visible-light regions. This work provides a comprehensive database of highly efficient light-emitting materials, which may be of interest for a broad field of optoelectronic applications.

All-fiber multifunction differential absorption CO2 lidar integrating single-photon and coherent detection.

This study demonstrates a differential absorption lidar (DIAL) for CO2 that integrates both single-photon direct detection and coherent detection. Based on all-fiber 1572 nm wavelength devices, this compact lidar achieves detection of CO2 concentration, wind field, and single photon aerosol backscattering signal. First, by comparing DIAL with VAISALA-GMP343, the concentration deviation between the two devices is less than 5 ppm, proving the accuracy of the DIAL. Second, through the scanning detection experiment in Chaohu Lake, Hefei, not only the CO2 concentration between single-photon detection and coherent detection but also the wind field was obtained, proving the multifunctionality and stability of the DIAL. Benefiting from the advantages of combined the two detection methods, single photon detection offers 3-km CO2 and aerosol backscattering signals; coherent detection offers a 360-m shorter blind zone and wind field. This DIAL can achieve monitoring of CO2 flux and sudden emissions, which can effectively compensate for the shortages of in-situ sensors and spaceborne systems.

Quantifying HONO Production from Nitrate Photolysis in a Polluted Atmosphere.

The photolysis of particulate nitrate (pNO3-) has been suggested to be an important source of nitrous acid (HONO) in the troposphere. However, determining the photolysis rate constant of pNO3- (jpNO3-) suffers from high uncertainty. Prior laboratory measurements of jpNO3- using aerosol filters have been complicated by the "shadow effect"─a phenomenon of light extinction within aerosol layers that potentially skews these measurements. We developed a method to correct the shadow effect on the photolysis rate constant of pNO3- for HONO production (jpNO3- â†’ HONO) using aerosol filters with identical chemical compositions but different aerosol loadings. We applied the method to quantify jpNO3- â†’ HONO over the North China Plain (NCP) during the winter haze period. After correcting for the shadow effect, the normalized average jpNO3- â†’ HONO at 5 °C increased from 5.89 × 10-6 s-1 to 1.72 × 10-5 s-1. The jpNO3- â†’ HONO decreased with increasing pH and nitrate proportions in PM2.5 and had no correlation with nitrate concentrations. A parametrization for jpNO3- â†’ HONO was developed for model simulation of HONO production in NCP and similar environments.

Asynchronous characteristics of Feammox and iron reduction from paddy soils in Southern China.

Recently, the newly discovered anaerobic ammonium oxidation coupled with iron reduction (i.e., Feammox) has been proven to be a widespread nitrogen (N) loss pathway in ecosystems and has an essential contribution to gaseous N loss in paddy soil. However, the mechanism of iron-nitrogen coupling transformation and the role of iron-reducing bacteria (IRB) in Feammox were poorly understood. This study investigated the Feammox and iron reduction changes and microbial community evolution in a long-term anaerobic incubation by 15N isotope labeling combined with molecular biological techniques. The average rates of Feammox and iron reduction during the whole incubation were 0.25 ± 0.04 µg N g-1 d-1 and 40.58 ± 3.28 µg Fe g-1 d-1, respectively. High iron oxide content increased the Feammox rate, but decreased the proportion of Feammox-N2 in three Feammox pathways. RBG-13-54-9, Brevundimonas, and Pelomonas played a vital role in the evolution of microbial communities. The characteristics of asynchronous changes between Feammox and iron reduction were found through long-term incubation. IRB might not be the key species directly driving Feammox, and it is necessary to reevaluate the role of IRB in Feammox process.

Regulatory of salinity on assembly of activated sludge microbial communities and nitrogen transformation potential in industrial plants of the lower Yangtze River basin.

This study aims to thoroughly investigate the impact mode of salinity carried by industrial wastewater on the anaerobic-anoxic-oxic (A2O) sludge in wastewater treatment plants (WWTPs). Through comprehensive investigation of the A2O stage activated sludge (AS) from 19 industrial WWTPs in the downstream area of the Yangtze River, China, A total of 38 samples of anaerobic sludge and oxic sludge were collected and analyzed. We found that salinity stress significantly inhibits the growth of the AS community, particularly evident in the anaerobic sludge community. Furthermore, the high-saline environment induces changes in the structure and functional patterns of the AS community, leading to intensive interactions and resource exchanges among microorganisms. Halophilic microorganisms may play a crucial role in this process, significantly impacting the overall community structure, especially in the oxic sludge community. Additionally, salinity stress not only suppresses the nitrogen transformation potential of the AS but also leads to the accumulation of nitrite, thereby increasing the emission potential of both NO and N2O, exacerbating the greenhouse effect of the A2O process in industrial WWTPs. The findings of this study provide necessary theoretical support for maintaining the long-term stable operation of the A2O sludge system in industrial WWTPs, reducing carbon footprint, and improving nitrogen removal efficiency.

Ultrasound-activated prodrug-loaded liposome for efficient cancer targeting therapy without chemotherapy-induced side effects.

BACKGROUND: Off-targeted distribution of chemotherapeutic drugs causes severe side effects, further leading to poor prognosis and patient compliance. Ligand/receptor-mediated targeted drug delivery can improve drug accumulation in the tumor but it always attenuated by protein corona barriers. RESULTS: To address these problems, a radically different strategy is proposed that can leave the off-targeted drugs inactive but activate the tumor-distributed drugs for cancer-targeting therapy in a tumor microenvironment-independent manner. The feasibility and effectiveness of this strategy is demonstrated by developing an ultrasound (US)-activated prodrug-loaded liposome (CPBSN38L) comprising the sonosensitizer chlorin e6 (Ce6)-modified lipids and the prodrug of pinacol boronic ester-conjugated SN38 (PBSN38). Once CPBSN38L is accumulated in the tumor and internalized into the cancer cells, under US irradiation, the sonosensitizer Ce6 rapidly induces extensive production of intracellular reactive oxygen species (ROS), thereby initiating a cascade amplified ROS-responsive activation of PBSN38 to release the active SN38 for inducing cell apoptosis. If some of the injected CPBSN38L is distributed into normal tissues, the inactive PBSN38 exerts no pharmacological activity on normal cells. CPBSN38L exhibited strong anticancer activity in multiple murine tumor models of colon adenocarcinoma and hepatocellular carcinoma with no chemotherapy-induced side effects, compared with the standard first-line anticancer drugs irinotecan and topotecan. CONCLUSIONS: This study established a side-effect-evitable, universal, and feasible strategy for cancer-targeting therapy.

Influence of Early Cluster Nursing Intervention on Nursing Efficacy and Adverse Events in Patients with Severe Traumatic Brain Injury.

Patients with severe traumatic brain injury (sTBI) are at risk of adverse events (AEs) during hospitalization, and providing nursing interventions can help reduce the negative impact of AEs. This study primarily discusses the influence of early cluster nursing intervention on nursing efficacy and AEs in patients with sTBI. We enrolled 109 sTBI patients treated in the First Affiliated Hospital of Shanghai Jiao Tong University School of Medicine between October 2022 to June 2023. We grouped them as follows based on different nursing approaches: regular group (n=52) with routine nursing intervention and research group (n=57) with early cluster nursing intervention. Parameters such as nursing satisfaction, incidence of AEs (bed falls, agitation, indwelling needle withdrawal, and skin loss), and scores of Fugl-Meyer Assessment (FMA), Functional Independence Measure (FIM), Glasgow Coma Scale (GCS), National Institutes of Health Stroke Scale (NIHSS), and quality of life assessment instrument (QOL-100) were comparatively analyzed. The analysis showed a higher nursing satisfaction degree and a lower incidence of AEs in the research group compared with the regular group; in addition, FMA, FIM, GCS, and QOL-100 scores were higher in the research group versus the control group after nursing, while the NIHSS score was lower; all of these differences were statistically significant (P < .05). Therefore, early cluster nursing intervention is highly effective in the care of sTBI patients. It can effectively improve patients' nursing satisfaction and prevent AEs while enhancing their motor function, functional independence, consciousness, neurological function, and quality of life.

Multi-imaging platform for rhizosphere studies: Phosphorus and oxygen fluxes.

Rhizosphere is a soil volume of high spatio-temporal heterogeneity and intensive plant-soil-microbial interactions, for which visualization and process quantification is of highest scientific and applied relevance, but still very challenging. A novel methodology for quick assessment of two-dimensional distribution of available phosphorus (P) in rhizosphere was suggested, tested, and development up to the application platform. Available P was firstly trapped by an in-situ diffusive gradients in thin-films (DGT) sampler with precipitated zirconia as the binding gel, and subsequently, the loaded gel was analyzed with an optimized colorimetric imaging densitometry (CID). The imaging platform was established linking: i) DGT, ii) planar optode, and iii) soil zymography techniques to simultaneously determine available P, oxygen, and acid phosphatase in rhizosphere at sub-millimeter spatial scales. The DGT identified available P level in rice rhizosphere were spatially overlapping to the localized redox hotspots and phosphatase activity. The spatial relationship between available P and acid phosphatase activity was dependent on root development. The root radial oxygen loss (ROL) remained active during the experimental observations (2-3 days), while a flux of available P of 10 pg cm-2 s-1 was visualized within 2-3 mm of roots, confirming the correlative response of rice roots to oxygen secretion and P uptake. Summarizing, the established imaging platform is suitable to capture spatial heterogeneity and temporal dynamics of root activities, nutrient bioavailability, ROL and enzyme activities in rhizosphere.

Modular Assembly of Acridines by Integrating Photo-Excitation of o-Alkyl Nitroarenes with Copper-Promoted Cascade Annulation.

Acridine frameworks stand as pivotal architectural elements in pharmaceuticals and photocatalytic applications, owing to their chemical adaptability, biological activity, and unique excited-state dynamics. Conventional synthetic routes often entail specialized starting materials, anaerobic or moisture-free conditions, and elaborate multi-stage manipulations for incorporating diverse functionalities. Herein, we present a convergent approach integrating photo-excitation of readily available ortho-alkyl nitroarenes with copper-promoted cascade annulation. This innovative system enables an aerobic, one-pot reaction of o-alkyl nitroarenes with arylboronic acids, thereby streamlining the modular construction of a wide array of acridine dervatives with various functional groups. This encompasses symmetrical, unsymmetrical and polysubstituted varieties, some of which are otherwise exceptionally difficult to synthesize. Furthermore, it significantly improves the production of structurally varied acridinium salts, featuring enhanced photophysical properties, high excited state potentials (E*red = 2.08-3.15 V), and exhibiting superior performance in intricate photoredox transformations.

ST6GALNAC4 promotes hepatocellular carcinogenesis by inducing abnormal glycosylation.

Hepatocellular carcinoma (HCC) is one of the most lethal tumor types worldwide. Glycosylation has shown promise in the study of tumor mechanisms and treatment. The glycosylation status of HCC and the underlying molecular mechanisms are still not fully elucidated. Using bioinformatic analysis we obtained a more comprehensive characterization of glycosylation of HCC. Our analysis presented that high glycosylation levels might correlate with tumor progression and poor prognosis. Subsequent Experiments identified key molecular mechanisms for ST6GALNAC4 promoting malignant progression by inducing abnormal glycosylation. We confirmed the contribution of ST6GALNAC4 to proliferation, migration, and invasion in vitro and in vivo. Mechanistic studies revealed that ST6GALNAC4 may be induced abnormal TGFBR2 glycosylation, resulting in the higher protein levels of TGFBR2 and TGF[Formula: see text] pathway increased activation. Our study also provided a further understand of immunosuppressive function of ST6GALNAC4 through T antigen-galectin3+ TAMs axis. This study has provided one such possibility that galectin3 inhibitors might be an acceptable treatment choice for HCC patients with high T antigen expression.

A novel genome sequence of Jasminum sambac helps uncover the molecular mechanism underlying the accumulation of jasmonates.

Jasminum sambac is a well-known plant for its attractive and exceptional fragrance, the flowers of which are used to produce scented tea. Jasmonate (JA), an important plant hormone was first identified in Jasminum species. Jasmine plants contain abundant JA naturally, of which the molecular mechanisms of synthesis and accumulation are not clearly understood. Here, we report a telomere-to-telomere consensus assembly of a double-petal J. sambac genome along with two haplotype-resolved genomes. We found that gain-and-loss, positive selection, and allelic specific expression of aromatic volatile-related genes contributed to the stronger flower fragrance in double-petal J. sambac compared with single- and multi-petal jasmines. Through comprehensive comparative genomic, transcriptomic, and metabolomic analyses of double-petal J. sambac, we revealed the genetic basis of the production of aromatic volatiles and salicylic acid (SA), and the accumulation of JA under non-stress conditions. We identified several key genes associated with JA biosynthesis, and their non-stress related activities lead to extraordinarily high concentrations of JA in tissues. High JA synthesis coupled with low degradation in J. sambac results in accumulation of high JA under typical environmental conditions, similar to the accumulation mechanism of SA. This study offers important insights into the biology of J. sambac, and provides valuable genomic resources for further utilization of natural products.

Vindoline ameliorates intestinal barrier damage in Crohn's disease mice through MAPK signaling pathway.

Intestinal inflammation and intestinal barrier damage are important pathological changes in Crohn's disease (CD). Vindoline is a natural monomer with anti-inflammatory effects. We employed CD model mice to explore the effect of Vindoline on CD-like colitis and the possible mechanism. Il-10-deficient (Il-10-/- ) mice and wild-type (WT) mice (both aged 15 weeks, male) were used to explore the effect of Vindoline on colitis and intestinal barrier damage, as well as macrophage-mediated inflammation. Bone-marrow-derived macrophages (BMDMs) and colonic organoids from mice were used to explore the inhibitory effect of Vindoline on macrophage-mediated inflammation and the protective effect on inflammation-induced intestinal barrier damage as well as the possible mechanism. We found that Vindoline significantly ameliorated colitis in CD mice, as evidenced by increased weight change and colon length and decreased the colon macroscopic injury score, histological inflammatory score, and the expression of pro-inflammatory mediators. Vindoline also protected against intestinal barrier damage in CD mice. Furthermore, Vindoline inhibited macrophage-mediated inflammation and protected against inflammation-induced intestinal barrier damage in the coculture system. In addition, Vindoline ameliorated colitis in CD mice by protecting against inflammation-induced intestinal barrier damage, which may be caused by inhibition of MAPK signaling pathway. This protective effect suggests that Vindoline has potential value for clinical application in the treatment of CD.

Nickel-Catalyzed Acid Chlorides with Tetrasulfides for the Synthesis of Thioesters and Acyl Disulfides.

Herein, we report a novel method for the synthesis of thioesters and acyl disulfides via nickel-catalyzed reductive cross-electrophile coupling of acid chlorides with tetrasulfides. This approach for the synthesis of thioesters and acyl disulfides is convenient and practical under mild reaction conditions, relying on easy availability. In addition, a wide range of thioesters and acyl disulfides were obtained in medium to good yields with good functional group tolerance. Moreover, thioesters and acyl disulfides can also be prepared at the gram scale, indicating that they have certain potential for industrial application.

Ultrasensitive photoelectrochemical detection of glutathione based on the multifunctional catalytic properties of phosphotungstic acid.

A novel photoelectrochemical (PEC) sensor was constructed for the highly sensitive detection of reduced glutathione (GSH) based on the multiple catalytic properties of phosphotungstic acid (PTA). In this work, the catalytic properties of PTA were applied to PEC sensing for the first time and interpreted in detail. First, PTA as an electron acceptor can inhibit the complexation of photogenerated electron-hole pairs in p-Cu2O, thus significantly increasing the photogenerated current of p-type semiconductor material Cu2O. Secondly, when GSH is oxidized to oxidized glutathione (GSSG) by photogenerated holes on the photocathode, PTA is able to reduce GSSG to GSH by transferring protons, forming a redox cycle regeneration process of GSH. Finally, the relatively large amount of PTA in the background solution was able to pre-oxidize interfering substances such as L-cysteine and ascorbic acid, which improved the selectivity of the method. Under the optimal experimental conditions, the linear range of the PEC sensor response to GSH was 0.050-100 nmol L-1, with a detection limit as low as 0.017 nmol L-1 (S/N = 3), which can be applied to the detection of GSH content in cell lysate samples.

Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits.

BACKGROUND: Insights into the genetic basis of complex traits and disease in both human and livestock species have been achieved over the past decade through detection of genetic variants in genome-wide association studies (GWAS). A majority of such variants were found located in noncoding genomic regions, and though the involvement of numerous regulatory elements (REs) has been predicted across multiple tissues in domesticated animals, their evolutionary conservation and effects on complex traits have not been fully elucidated, particularly in ruminants. Here, we systematically analyzed 137 epigenomic and transcriptomic datasets of six mammals, including cattle, sheep, goats, pigs, mice, and humans, and then integrated them with large-scale GWAS of complex traits. RESULTS: Using 40 ChIP-seq datasets of H3K4me3 and H3K27ac, we detected 68,479, 58,562, 63,273, 97,244, 111,881, and 87,049 REs in the liver of cattle, sheep, goats, pigs, humans and mice, respectively. We then systematically characterized the dynamic functional landscapes of these REs by integrating multi-omics datasets, including gene expression, chromatin accessibility, and DNA methylation. We identified a core set (n = 6359) of ruminant-specific REs that are involved in liver development, metabolism, and immune processes. Genes with more complex cis-REs exhibited higher gene expression levels and stronger conservation across species. Furthermore, we integrated expression quantitative trait loci (eQTLs) and GWAS from 44 and 52 complex traits/diseases in cattle and humans, respectively. These results demonstrated that REs with different degrees of evolutionary conservation across species exhibited distinct enrichments for GWAS signals of complex traits. CONCLUSIONS: We systematically annotated genome-wide functional REs in liver across six mammals and demonstrated the evolution of REs and their associations with transcriptional output and conservation. Detecting lineage-specific REs allows us to decipher the evolutionary and genetic basis of complex phenotypes in livestock and humans, which may benefit the discovery of potential biomedical models for functional variants and genes of specific human diseases.