A Tumor-Activatable Liposomal Nanoprobe for Selective Visualization of Metastatic Lymph Nodes.

The precise identification of sentinel lymph nodes (SLNs) during surgery and assessment of their benign status is crucial for accurate tumor staging and optimal treatment strategizing. Currently, a deficiency exists in non-invasive in vivo diagnostic techniques that can accurately pinpoint SLNs during surgery while simultaneously evaluating their benign status. Here, a tumor-activatable liposomal nanoprobe (nTAL) is developed, remotely loaded with clinically approved photosensitizer, methyl aminolevulinate (MAL), to noninvasively visualize the tumor metastasis lymph nodes (LNs) with precision. Benefited from the highly efficient LNs draining of nanosized liposome and tumor cell-specific transformation of the non-fluorescent MAL to fluorescent protoporphyrin IX (PPIX), nTAL succeeded in targeting the SLNs and differentiated the metastatic from the benign ones with a positive correlation between PPIX generation and tumor cell infiltration in LNs. Moreover, the nTAL technology is capable of probing the early metastatic stage with a primary tumor size of 50 mm3. This study provides a new strategy for intraoperative visualization of real-time sentinel node dissection.

Radial Oxygen Loss Triggers Diel Fluctuation of Cadmium Dissolution in the Rhizosphere of Rice.

Cadmium (Cd) contamination poses a significant global threat to human health, primarily through dietary intake, with rice serving as a major source. While Cd predominantly resides in bound states in soil, the physiological processes by which rice facilitates Cd absorption in the rhizosphere remain largely elusive. This study delves into the mechanisms governing Cd uptake by rice plants in the rhizosphere, emphasizing the impact of daytime and nighttime fluctuations in microenvironmental conditions. Employing a microfluidic chip setup, the research reveals that radial oxygen loss from rice roots triggers dissolution of Cd in the rhizosphere. Notably, Cd mobility exhibits distinct diurnal fluctuations, peaking at 44.0 ± 4.1 nM during the daytime and dropping to 8.3 ± 1.3 nM during the nighttime. Further investigations reveal that variations in dissolved oxygen and hydroxyl radical concentrations influence Cd release, while pH changes and microbial reduction reactions play crucial roles in Cd immobilization. These findings provide insights into the intricate processes governing Cd mobilization in the rice rhizosphere, highlighting the importance of regulating these processes for effective Cd adsorption control in rice crops and safeguarding public health.

Deciphering the functional assembly of microbial communities driven by heavy metals in the tidal soils of Hangzhou Bay.

Understanding the interaction between heavy metals and soil microbiomes is essential for maintaining ecosystem health and functionality in the face of persistent human-induced challenges. This study investigated the complex relationships between heavy metal contamination and the functional characteristics of soil microbial communities in the tidal soils of Hangzhou Bay, a region experiencing substantial environmental pressure due to its proximity to densely populated and industrialized regions. The north-shore sampling site showed moderate contaminations (mg/kg) of total arsenic (16.61 ± 1.13), cadmium (0.3 ± 0.05), copper (31.28 ± 1.23), nickel (37.44 ± 2.74), lead (34.29 ± 5.99), and zinc (120.8 ± 5.96), which are 1.29-2.94 times higher than the geochemical background values in Hangzhou Bay and adjacent areas. In contrast, the south-shore sampling site showed slightly higher levels of total arsenic (13.76 ± 1.35) and cadmium (0.13 ± 0.02) than the background values. Utilizing metagenomic sequencing, we decoded microbial functional genes essential for nitrogen, phosphorus, sulfur, and methane biogeochemical cycles. Although soil available nickel content was relatively low at 1 mg/kg, it exhibited strong associations with diverse microbial genes and biogeochemical pathways. Four key genes-hxlB, glpX, opd, and phny-emerged as pivotal players in the interactions with available nickel, suggesting the adaptability of microbial metabolic responses to heavy metal. Additionally, microbial genera such as Gemmatimonas and Ilumatobacter, which harbored diverse functional genes, demonstrated potential interactions with soil nickel. These findings highlight the importance of understanding heavy metal-soil microbiome dynamics for effective environmental management strategies in the tidal soils of Hangzhou Bay, with the goal of preserving ecosystem health and functionality amidst ongoing anthropogenic challenges.

Temperature-dependent trophic associations modulate soil bacterial communities along latitudinal gradients.

Understanding the environmental and biological mechanisms shaping latitudinal patterns in microbial diversity is challenging in the field of ecology. Although multiple hypotheses have been proposed to explain these patterns, a consensus has rarely been reached. Here, we conducted a large-scale field survey and microcosm experiments to investigate how environmental heterogeneity and putative trophic interactions (exerted by protist-bacteria associations and T4-like virus-bacteria associations) affect soil bacterial communities along a latitudinal gradient. We found that the microbial latitudinal diversity was kingdom dependent, showing decreasing, clumped, and increasing trends in bacteria, protists, and T4-like viruses, respectively. Climatic and edaphic drivers played predominant roles in structuring the bacterial communities, the intensity of the climatic effect increased sharply from 30°N to 32°N, whereas the intensity of the edaphic effect remained stable. Biotic associations were also essential in shaping the bacterial communities, with protist-bacteria associations showing a quadratic distribution, whereas virus-bacteria associations were significant only at high latitudes. The microcosm experiments further revealed that the temperature component, which is affiliated with climate conditions, is the primary regulator of trophic associations along the latitudinal gradient. Overall, our study highlights a previously underestimated mechanism of how the putative biotic interactions influence bacterial communities and their response to environmental gradients.

Stereoselective Construction of Multifunctional C-Glycosides Enabled by Nickel-Catalyzed Tandem Borylation/Glycosylation.

Stereochemically pure saccharides have indispensable roles in fields ranging from medicinal chemistry to materials science and organic synthesis. However, the development of a simple, stereoselective, and efficient glycosylation protocol to access α- and ß-C-glycosides (particularly 2-deoxy entities) remains a persistent challenge. Existing studies have primarily focused on C1 modification of carbohydrates and transformation of glycosyl radical precursors. Here, we innovate by harnessing the in situ generated glycosyl-Ni species to achieve one-pot borylation and glycosylation in a cascade manner, which is enabled by an earth-abundant nickel-catalyzed carboboration of readily accessible glycals without any ligand. This work reveals the potential for the development of a modular and multifunctional glycosylation platform to facilitate the simultaneous introduction of C-C and C-B bonds at the stereogenic center of saccharides, a largely unexploited research area. Preliminary experimental and computational studies indicate that the endocyclic O and the C3 group play important roles in stereoseclectively forging glycosidic bonds. As a result, a diverse range of C-R (R = alkyl, aryl, and alkenyl) and 2-deoxygenated glycosides bearing modifiable boron groups could be rapidly made with excellent stereocontrol and exhibit remarkable functional group tolerance. The synthetic potential is underscored in the late-stage glycosylation of natural products and commercial drugs as well as the facile preparation of various rare sugars, bioactive conjugates, and key intermediates to prorocentin, phomonol, and aspergillide A.

Prenatal Diagnosis of Persistent Left Superior Vena Cava Using High-Definition Flow Render Mode and Spatiotemporal Image Correlation.

OBJECTIVE: This study aimed to assess the use of two-dimensional (2D) ultrasound combined with high-definition flow (HD-flow) render mode and spatiotemporal image correlation (STIC) in diagnosing and classifying fetal persistent left superior vena cava (PLSVC). METHODS: Overall, 114 cases of fetal PLSVC were diagnosed using 2D ultrasound combined with STIC, and 114 normal fetuses of the same gestational week were selected. These cases were retrospectively analyzed to evaluate the effectiveness of the diagnostic approach. RESULTS: All 114 PLSVC cases were diagnosed using 2D ultrasound combined with STIC. Although the diagnostic coincidence rate of PLSVC in the HD-flow combined with STIC was similar to that in the 2D ultrasound combined with HD-flow (96.8 vs 96.2%), 2D ultrasound with STIC enabled dynamic visualization of the PLSVC, furthering prenatal diagnosis. These cases were classified as type I PLSVC: 80 cases of type Ia, 29 cases of type Ib, and 5 cases of type Ic. Seventy isolated PLSVC cases (61.4%) were noted, whereas 44 cases (35.6%) were associated with concomitant structural abnormalities. Intracardiac structural malformations accounted for the highest proportion (n = 53, 58.89%), followed by single umbilical artery and facial/bodily abnormalities (n = 10, 11.11%). CONCLUSION: Combining HD-flow and STIC complements 2D ultrasound in diagnosing and classifying fetal PLSVC, demonstrating significant clinical relevance.

Aspirin Inhibits Colorectal Cancer via the TIGIT-BCL2-BAX pathway in T Cells.

The T cell immunoglobulin and ITAM domain (TIGIT) is a recently discovered synergistic co-suppressor molecule that plays an important role in immune response and tumor immune escape in the context of cancer. Importantly, CD155 acts as a receptor for TIGIT, and CD155 signaling to immune cells is mediated through interactions with the co-stimulatory immune receptor CD226 (DNAM-1) and the inhibitory checkpoint receptors TIGIT and CD96. Aspirin (ASA) has been shown to reduce the growth and survival of colorectal cancer (CRC) cells, but the immunological mechanisms involved have not been sufficiently elucidated. In the present study the effects of aspirin on CRC in mice and on Jurkat cells were investigated. Aspirin may suppress the expression of TIGIT on T cells and Regulatory T cells (Tregs) and inhibit T cell viability, and therefore induce tumor cell apoptosis. TIGIT is expressed at higher levels on infiltrating lymphocytes within CRC tumor tissue than adjacent. Further, aspirin could inhibit Jurkat cell proliferation and induce apoptosis via downregulation of TIGIT expression and the anti-apoptosis B cell lymphoma 2 (BCL2) protein and upregulation of BCL2-associated X protein (BAX) expression. The present study suggests that aspirin can inhibit specific aspects of T cell function by reducing interleukin-10 and transforming growth factor-ß1 secretion via the TIGIT-BCL2-BAX signaling pathway, resulting in improved effector T cell function that inhibits tumor progression.

Genetic improvement of phosphate-limited photosynthesis for high yield in rice.

Low phosphate (Pi) availability decreases photosynthesis, with phosphate limitation of photosynthesis occurring particularly during grain filling of cereal crops; however, effective genetic solutions remain to be established. We previously discovered that rice phosphate transporter OsPHO1;2 controls seed (sink) development through Pi reallocation during grain filling. Here, we find that OsPHO1;2 regulates Pi homeostasis and thus photosynthesis in leaves (source). Loss-of-function of OsPHO1;2 decreased Pi levels in leaves, leading to decreased photosynthetic electron transport activity, CO2 assimilation rate, and early occurrence of phosphate-limited photosynthesis. Interestingly, ectopic expression of OsPHO1;2 greatly increased Pi availability, and thereby, increased photosynthetic rate in leaves during grain filling, contributing to increased yield. This was supported by the effect of foliar Pi application. Moreover, analysis of core rice germplasm resources revealed that higher OsPHO1;2 expression was associated with enhanced photosynthesis and yield potential compared to those with lower expression. These findings reveal that phosphate-limitation of photosynthesis can be relieved via a genetic approach, and the OsPHO1;2 gene can be employed to reinforce crop breeding strategies for achieving higher photosynthetic efficiency.

Biotransformation research advances - 2023 year in review.

This annual review marks the eighth in the series starting with Baillie et al. (2016) Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation. Its format is to highlight important aspects captured in synopsis followed by a commentary with relevant figure and references.

Accelerated clinical response achieved by combining short-term tumor-directed photodynamic therapy with immunotherapy-based systemic therapies in synchronous colorectal cancer with MSI-H and POLE mutation: a case report.

Genetic sequencing has revolutionized immunotherapy in colorectal cancer (CRC). Recent clinical trials have revealed a positive response to immunotherapy-based systemic therapies in CRC patient subgroups with microsatellite instability (MSI)-High or DNA polymerase epsilon (POLE) mutation. However, the unsatisfactory response rates was the major limitation in real-world practice of the precision immunotherapy in CRC. Adding photodynamic therapy (PDT) to systemic immunotherapy has showed synergetic anti-tumor effect by modulating tumor microenvironment, while the eligible patient's subgroups which would benefit from this combination remained equivocal. Here we reported a synchronous colorectal cancer patient with MSI-High and POLE mutation who had accelerated response in less than 2 cycles (42 days) of immunotherapy-based systemic therapies after tumor-directed PDT and has remained progression-free by far. This case enlightened the synergetic effect of PDT in immunotherapy-treated CRC patients, with the MSI and POLE-mutation status as predictors of survival benefits.

Bioactivation and reactivity research advances - 2023 year in review.

Advances in the field of bioactivation have significantly contributed to our understanding and prediction of drug-induced liver injury (DILI). It has been established that many adverse drug reactions, including DILI, are associated with the formation and reactivity of metabolites. Modern methods allow us to detect and characterize these reactive metabolites in earlier stages of drug development, which helps anticipate and circumvent the potential for DILI. Improved in silico models and experimental techniques that better reflect in vivo environments are enhancing predictive capabilities for DILI risk. Further, studies on the mechanisms of bioactivation, including enzyme interactions and the role of individual genetic differences, have provided valuable insights for drug optimizations. Cumulatively, this progress is continually refining our approaches to drug safety evaluation and personalized medicine.

Host-virus coevolution drives soil microbial function succession along a millennium land reclamation chronosequence.

INTRODUCTION: Gene exchange between viruses and hosts plays an important role in driving virus-host coevolution, enabling adaptation of both viruses and hosts to environmental changes. However, the mechanisms and functional significance of virus-host gene exchanges over long-term scales remain largely unexplored. OBJECTIVE: The present study aimed to gain insights into the role of viruses in virus-host interactions and coevolution by monitoring virome dynamics along a millennium-long land reclamation chronosequence. METHODS: We collected 24 soil samples from 8 stages of a millennium-long land reclamation chronosequence, including non-reclamation, and reclamation periods of 10, 50, 100, 300, 500, 700, and 1000 years. We characterized their metagenomes, and identified DNA viruses within these metagenomes. RESULTS: Our findings reveal a significant shift in viral community composition after 50 years of land reclamation, but soil viral diversity reached a stable phase approximately 300 years after the initial reclamation. Analysis of the virus-host network showed a scale-free degree distribution and a reduction in complexity over time, with generalist viruses emerging as key facilitators of horizontal gene transfer. CONCLUSION: These findings highlight the integral role of viruses, especially generalist types, in mediating gene exchanges between viruses and hosts, thereby influencing the coevolutionary dynamics in soil ecosystems over significant timescales. This study offers novel insights into long-term virus-host interactions, showing how the virome responds to environmental changes, driving shifts in various microbial functions in reclaimed land.

Multi-heteroatom doped nanographenes: enhancing photosensitization capacity by forming an electron donor-acceptor architecture.

Systematically tuning and optimizing the properties of synthetic nanographenes (NGs) is particularly important for NG applications in diverse areas. Herein, by devising novel electron donor-acceptor (D-A) type structures, we reported a series of multi-heteroatom-doped NGs possessing an electron-rich chalcogen and electron-deficient pyrimidine or pyrimidinium rings. Comprehensive experimental and theoretical investigations revealed significantly different physical, optical, and energetic properties compared to the non-doped HBC or chalcogen-doped, non-D-A analogues. Some intriguing properties of the new NGs such as unique electrostatically oriented molecular stacking, red-shifted optical spectra, solvatochromism, and enhanced triplet excitons were observed due to the formation of the D-A electron pattern. More importantly, these D-A type structures can serve as photosensitizers to generate efficiently reactive-oxygen species (ROS), and the structure-related photosensitization capacity that strengthens the electron transfer (ET) process leads to significantly enhanced ROS which was revealed by experimental and calculated studies. As a result, the cell-based photodynamic therapy (PDT) indicated that the cationic NG 1-Me+ is a robust photosensitizer with excellent water-solubility and biocompatibility.

Identification of diagnostic signature and immune infiltration for ischemic cardiomyopathy based on cuproptosis-related genes through bioinformatics analysis and experimental validation.

BACKGROUND: Ischemic cardiomyopathy (IC) is primarily due to long-term ischemia/hypoxia of the coronary arteries, leading to impaired cardiac contractile or diastolic function. A new form of cell death induced by copper, called "cuproptosis" is related to the development and progression of multiple diseases. The cuproptosis-related gene (CuGs) plays an important role in acute myocardial infarction, while the specific mechanisms of CuGs in ischemic cardiomyopathy remain unclear. METHODS: The expressions of CuGs and their immune characteristics were analyzed with the IC datasets obtained from the Gene Expression Omnibus, namely GSE5406 and GSE57338, identifying core genes associated with IC development. By comparing RF, SVM, GLM and XGB models, the optimal machine learning model was selected. The expression of marker genes was validated based on the GSE57345, GSE48166 and GSE42955 datasets. Construct a CeRNA network based on core genes. Therapeutic chemiacals targeting core genes were acquired using the CTD database, and molecular docking was performed using Autodock vina software. By ligating the left anterior descending (LAD) coronary artery, an IC mouse model is established, and core genes were experimentally validated using Western blot (WB) and immunohistochemistry (IHC) methods. RESULTS: We identified 14 CuGs closely associated with the onset of IC. The SVM model exhibited superior discriminative power (AUC = 0.914), with core genes being DLST, ATP7B, FDX1, SLC31A1 and DLAT. Core genes were validated on the GSE42955, GSE48166 and GSE57345 datasets, showing excellent performance (AUC = 0.943, AUC = 0.800, and AUC = 0.932). The CeRNA network consists of 218 nodes and 264 lines, including 5 core diagnostic genes, 52 miRNAs, and 161 lncRNAs. Chemicals predictions indicated 8 chemicals have therapeutic effects on the core diagnostic genes, with benzo(a)pyrene molecular docking showing the highest affinity (-11.3 kcal/mol). Compared to the normal group, the IC group,which was established by LAD ligation, showed a significant decrease in LVEF as indicated by cardiac ultrasound, and increased fibrosis as shown by MASSON staining, WB results suggest increased expression of DLST and ATP7B, and decreased expression of FDX1, SLC31A1 and DLAT in the myocardial ischemic area (p < 0.05), which was also confirmed by IHC in tissue sections. CONCLUSION: In summary, this study comprehensively revealed that DLST, ATP7B, FDX1, SLC31A1 and DLAT could be identified as potential immunological biomarkers in IC, and validated through an IC mouse model, providing valuable insights for future research into the mechanisms of CuGs and its diagnostic value to IC.

Analysis of lettuce transcriptome reveals the mechanism of different light/dark cycle in promoting the growth and quality.

Light/dark (L/D) cycle plays a crucial role in controlling the production and quality of vegetables. However, the mechanism of L/D cycle on vegetable growth and quality is scarce studied. To investigate the impact of L/D cycle on lettuce growth and quality, we designed three diel scenarios, including 16 hours of light and 8 hours of darkness (L16/D8), 12 hours of light and 6 hours of darkness (L12/D6), and 8 hours of light and 4 hours of darkness (L8/D4). By phenotypic analysis, we found that lettuce grew taller under the L8/D4 scenario than under L16/D8 light cycle scenarios. The physiological indexes showed that the lettuce leaves grown in the L8/D4 scenario exhibited greater enhancements in the levels of soluble protein, soluble sugar, and carotenoid content compared to the other scenarios. By comparing the expression levels under different diel scenarios (L16/D8 vs L12/D6, L16/D8 vs L8/D4, and L12/D6 vs L8/D4), we identified 7,209 differentially expressed genes (DEGs). Additionally, 3 gene modules that were closely related to L/D cycle of lettuce were selected by WGCNA analysis. The eigengenes of three gene modules were enriched in plant hormone signal transduction, sphingolipid metabolism, and nucleocytoplasmic transport pathways. Through network analysis, we identified six hub genes (CIP1, SCL34, ROPGEF1, ACD6, CcmB, and Rps4) in the three gene modules, which were dominant in plant circadian rhythms and greatly affected lettuce growth. qRT-PCR analysis confirmed the diurnal response patterns of the 6 hub genes in different treatments were significant. This study intensively enhanced our comprehension of the L/D cycle in the growth morphology, nutritional quality, and metabolic pathways of lettuce.

Spatial proximity and gene function: a new dimension in prokaryotic gene association network analysis with 3D-GeneNet.

Understanding the biological functions and processes of genes, particularly those not yet characterized, is crucial for advancing molecular biology and identifying therapeutic targets. The hypothesis guiding this study is that the 3D proximity of genes correlates with their functional interactions and relevance in prokaryotes. We introduced 3D-GeneNet, an innovative software tool that utilizes high-throughput sequencing data from chromosome conformation capture techniques and integrates topological metrics to construct gene association networks. Through a series of comparative analyses focused on spatial versus linear distances, we explored various dimensions such as topological structure, functional enrichment levels, distribution patterns of linear distances among gene pairs, and the area under the receiver operating characteristic curve by utilizing model organism Escherichia coli K-12. Furthermore, 3D-GeneNet was shown to maintain good accuracy compared to multiple algorithms (neighbourhood, co-occurrence, coexpression, and fusion) across multiple bacteria, including E. coli, Brucella abortus, and Vibrio cholerae. In addition, the accuracy of 3D-GeneNet's prediction of long-distance gene interactions was identified by bacterial two-hybrid assays on E. coli K-12 MG1655, where 3D-GeneNet not only increased the accuracy of linear genomic distance tripled but also achieved 60% accuracy by running alone. Finally, it can be concluded that the applicability of 3D-GeneNet will extend to various bacterial forms, including Gram-negative, Gram-positive, single-, and multi-chromosomal bacteria through Hi-C sequencing and analysis. Such findings highlight the broad applicability and significant promise of this method in the realm of gene association network. 3D-GeneNet is freely accessible at https://github.com/gaoyuanccc/3D-GeneNet.

Discovery of GS-7682, a Novel 4'-Cyano-Modified C-Nucleoside Prodrug with Broad Activity against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys.

Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1), a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad antiviral activity against RSV (EC50 = 3-46 nM), human metapneumovirus (EC50 = 210 nM), human rhinovirus (EC50 = 54-61 nM), and enterovirus (EC50 = 83-90 nM). Prodrug optimization for cellular potency and lung cell metabolism identified 5'-methyl [(S)-hydroxy(phenoxy)phosphoryl]-l-alaninate in combination with 2',3'-diisobutyrate promoieties as being optimal for high levels of intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together, these findings support additional evaluation of 1 and its analogues as potential therapeutics for pneumo- and picornaviruses.

Spatial Chromosome Organization and Adaptation of Escherichia coli under Heat Stress.

The spatial organization of bacterial chromosomes is crucial for cellular functions. It remains unclear how bacterial chromosomes adapt to high-temperature stress. This study delves into the 3D genome architecture and transcriptomic responses of Escherichia coli under heat-stress conditions to unravel the intricate interplay between the chromosome structure and environmental cues. By examining the role of macrodomains, chromosome interaction domains (CIDs), and nucleoid-associated proteins (NAPs), this work unveils the dynamic changes in chromosome conformation and gene expression patterns induced by high-temperature stress. It was observed that, under heat stress, the short-range interaction frequency of the chromosomes decreased, while the long-range interaction frequency of the Ter macrodomain increased. Furthermore, two metrics, namely, Global Compactness (GC) and Local Compactness (LC), were devised to measure and compare the compactness of the chromosomes based on their 3D structure models. The findings in this work shed light on the molecular mechanisms underlying thermal adaptation and chromosomal organization in bacterial cells, offering valuable insights into the complex inter-relationships between environmental stimuli and genomic responses.