Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS.

RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localization and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain and preventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.

TDO2-overexpressed Dendritic Cells Possess Tolerogenicity and Ameliorate Collagen-induced Arthritis by Modulating the Th17/Regulatory T Cell Balance.

Tolerogenic dendritic cells are promising for restoring immune homeostasis and may be an alternative therapy for autoimmune diseases such as rheumatoid arthritis. The kynurenine pathway is a vital mechanism that induces tolerance in dendritic cells (DCs). Tryptophan 2,3-dioxygenase (TDO2) is an important rate-limiting enzyme in the kynurenine pathway and participates in immune regulation. However, the role of TDO2 in shaping the tolerogenic phenotypes of DCs remains unclear. In this study, we investigated the effects and mechanisms of TDO2-overexpressed DCs in regulating the T cell balance both in vivo and in vitro. TDO2-overexpressed DC2.4 and TDO2-/- mouse bone marrow-derived DCs (BMDCs) were generated to verify the role of TDO2 in DC maturation and functionality. TDO2 overexpression in BMDCs via PGE2 treatment exhibited an immature phenotype and tolerogenic state, whereas TDO2-/- BMDCs exhibited a mature phenotype and a proinflammatory state. Furthermore, transplant of TDO2-overexpressed BMDCs alleviated collagen-induced arthritis severity in mice, which was correlated with a reduction in Th17 populations and an increase in regulatory T cells. Collectively, these results indicate that TDO2 plays an important role in the tolerogenic phenotype and may be a promising target for the generation tolerogenic DCs for rheumatoid arthritis treatment.

A bio-orthogonal linear ubiquitin probe identifies STAT3 as a direct substrate of OTULIN in glioblastoma.

While linear ubiquitin plays critical roles in multiple cell signaling pathways, few substrates have been identified. Global profiling of linear ubiquitin substrates represents a significant challenge because of the low endogenous level of linear ubiquitination and the background interference arising from highly abundant ubiquitin linkages (e.g. K48- and K63-) and from the non-specific attachment of interfering proteins to the linear polyubiquitin chain. We developed a bio-orthogonal linear ubiquitin probe by site-specific encoding of a norbornene amino acid on ubiquitin (NAEK-Ub). This probe facilitates covalent labeling of linear ubiquitin substrates in live cells and enables selective enrichment and identification of linear ubiquitin-modified proteins. Given the fact that the frequent overexpression of the linear linkage-specific deubiquitinase OTULIN correlates with poor prognosis in glioblastoma, we demonstrated the feasibility of the NAEK-Ub strategy by identifying and validating substrates of linear ubiquitination in patient-derived glioblastoma stem-like cells (GSCs). We identified STAT3 as a bona fide substrate of linear ubiquitin, and showed that linear ubiquitination negatively regulates STAT3 activity by recruitment of the phosphatase TC-PTP to STAT3. Furthermore, we demonstrated that preferential expression of OTULIN in GSCs restricts linear ubiquitination on STAT3 and drives persistent STAT3 signaling, and thereby maintains the stemness and self-renewal of GSCs.

Organ-Specific Gene Expression Control Using DNA Origami-Based Nanodevices.

Nanodevices that function in specific organs or cells are one of the ultimate goals of synthetic biology. The recent progress in DNA nanotechnology such as DNA origami has allowed us to construct nanodevices to deliver a payload (e.g., drug) to the tumor. However, delivery to specific organs remains difficult due to the fragility of the DNA nanostructure and the low targeting capability of the DNA nanostructure. Here, we constructed tough DNA origami that allowed us to encapsulate the DNA origami into lipid-based nanoparticles (LNPs) under harsh conditions (low pH), harnessing organ-specific delivery of the gene of interest (GOI). We found that DNA origami-encapsulated LNPs can increase the functionality of payload GOIs (mRNA and siRNA) inside mouse organs through the contribution from different LNP structures revealed by cryogenic electron microscope (Cryo-EM). These data should be the basis for future organ-specific gene expression control using DNA origami nanodevices.

Enantiospecific Analysis of Carboxylic Acids Using Cinchona Alkaloid Dimers as Chiral Solvating Agents.

Cinchona alkaloid derivatives as Brønsted base catalysts have attracted considerable attention in the field of asymmetric catalysis. However, their potential application as chiral solvating agents has not been described. In this research, we investigated the use of the Cinchona alkaloid dimer, namely, (DHQ)2PHAL, as a chiral solvating agent for discerning various mandelic acid derivatives through 1H NMR spectroscopy. The addition of catalytic amounts of DMAP facilitated this process. Our experimental results demonstrate that dimeric (DHQ)2PHAL exhibits remarkable chiral discrimination properties regarding the diagnostic split protons of 1H NMR signals (including 24 examples, up to 0.321 ppm). Furthermore, it serves as an excellent chiral discriminating agent and provides good resolution for racemic chiral phosphoric acid as determined by 31P NMR spectroscopy. The quality of enantiodifferentiation has also been evaluated by means of the parameter "resolution (Rs)". Significantly, this class of CSAs based on (alkaloid)2linker systems with an azaaromatic linker can be directly employed, which is commercially available in an enantiopure form at very low cost and exhibits promising potential in determining the enantiopurity of α-hydroxy acids by chemoselective and biocatalytic reactions.

Hepcidin deficiency impairs hippocampal neurogenesis and mediates brain atrophy and memory decline in mice.

BACKGROUND: Hepcidin is the master regulator of iron homeostasis. Hepcidin downregulation has been demonstrated in the brains of Alzheimer's disease (AD) patients. However, the mechanism underlying the role of hepcidin downregulation in cognitive impairment has not been elucidated. METHODS: In the present study, we generated GFAP-Cre-mediated hepcidin conditional knockout mice (HampGFAP cKO) to explore the effect of hepcidin deficiency on hippocampal structure and neurocognition. RESULTS: We found that the HampGFAP cKO mice developed AD-like brain atrophy and memory deficits. In particular, the weight of the hippocampus and the number of granule neurons in the dentate gyrus were significantly reduced. Further investigation demonstrated that the morphological change in the hippocampus of HampGFAP cKO mice was attributed to impaired neurogenesis caused by decreased proliferation of neural stem cells. Regarding the molecular mechanism, increased iron content after depletion of hepcidin followed by an elevated level of the inflammatory factor tumor necrosis factor-α accounted for the impairment of hippocampal neurogenesis in HampGFAP cKO mice. These observations were further verified in GFAP promoter-driven hepcidin knockdown mice and in Nestin-Cre-mediated hepcidin conditional knockout mice. CONCLUSIONS: The present findings demonstrated a critical role for hepcidin in hippocampal neurogenesis and validated the importance of iron and associated inflammatory cytokines as key modulators of neurodevelopment, providing insights into the potential pathogenesis of cognitive dysfunction and related treatments.

Continuous planting of euhalophyte Suaeda salsa enhances microbial diversity and multifunctionality of saline soil.

Halophyte-based remediation emerges as a novel strategy for ameliorating saline soils, offering a sustainable alternative to conventional leaching methods. While bioremediation is recognized for its ability to energize soil fertility and structure, the complex interplays among plant traits, soil functions, and soil microbial diversity remain greatly unknown. Here, we conducted a 5-year field experiment involving the continuous cultivation of the annual halophyte Suaeda salsa in saline soils to explore soil microbial diversity and their relationships with plant traits and soil functions. Our findings demonstrate that a decline in soil salinity corresponded with increases in the biomass and seed yield of S. salsa, which sustained a consistent seed oil content of approximately 22% across various salinity levels. Significantly, prolonged cultivation of halophytes substantially augmented soil microbial diversity, particularly from the third year of cultivation. Moreover, we identified positive associations between soil multifunctionality, seed yield, and taxonomic richness within a pivotal microbial network module. Soils enriched with taxa from this module showed enhanced multifunctionality and greater seed yields, correlating with the presence of functional genes implicated in nitrogen fixation and nitrification. Genomic analysis suggests that these taxa have elevated gene copy numbers of crucial functional genes related to nutrient cycling. Overall, our study emphasizes that the continuous cultivation of S. salsa enhances soil microbial diversity and recovers soil multifunctionality, expanding the understanding of plant-soil-microbe feedback in bioremediation.IMPORTANCEThe restoration of saline soils utilizing euhalophytes offers a viable alternative to conventional irrigation techniques for salt abatement and soil quality enhancement. The ongoing cultivation of the annual Suaeda salsa and its associated plant traits, soil microbial diversity, and functionalities are, however, largely underexplored. Our investigation sheds light on these dynamics, revealing that cultivation of S. salsa sustains robust plant productivity while fostering soil microbial diversity and multifunctionality. Notably, the links between enhanced soil multifunctionality, increased seed yield, and network-dependent taxa were found, emphasizing the importance of key microbial taxa linked with functional genes vital to nitrogen fixation and nitrification. These findings introduce a novel understanding of the role of soil microbes in bioremediation and advance our knowledge of the ecological processes that are vital for the rehabilitation of saline environments.

Azimuthal polarized quasi-bound states in the continuum based on rotational symmetry breaking.

Bound states in the continuum (BICs) allow to obtain an ultrahigh-quality-factor optical cavity. Nevertheless, BICs must be extended in one or more directions, substantially increasing the device footprint. Although super-cavity mode quasi-BICs supported by single nanopillars have been demonstrated recently, their low-quality factor and localized electromagnetic field inside the dielectric nanopillar are insufficient for high-sensitivity refractive index sensing applications. We propose a ring structure rotated by a dielectric sectorial nanostructure, which can achieve a high quality factor by breaking the rotational symmetry of the ring structure with a footprint as small as 3 µm2. As a straightforward application, we demonstrate high performance local refractive index and nanoscale film thickness sensing based on rotational symmetry breaking induced BICs. These BICs reach quality factor and sensitivity of one order of magnitude better than those of conventional super-cavity mode BICs. The proposed method provides insights into the design of compact high quality factor photonic devices, opening up new possibilities for applications in refractive index and nanoscale film thickness sensing.

Male vitellogenin regulates gametogenesis through a testis-enriched big protein in Chrysopa pallens.

In insects, vitellogenin (Vg) is generally viewed as a female-specific protein. Its primary function is to supply nutrition to developing embryos. Here, we reported Vg from the male adults of a natural predator, Chrysopa pallens. The male Vg was depleted by RNAi. Mating with Vg-deficient male downregulated female Vg expression, suppressed ovarian development and decreased reproductive output. Whole-organism transcriptome analysis after male Vg knockdown showed no differential expression of the known spermatogenesis-related regulators and seminal fluid protein genes, but a sharp downregulation of an unknown gene, which encodes a testis-enriched big protein (Vcsoo). Separate knockdown of male Vg and Vcsoo disturbed the assembly of spermatid cytoplasmic organelles in males and suppressed the expansion of ovary germarium in mated females. These results demonstrated that C. pallens male Vg signals through the downstream Vcsoo and regulates male and female reproduction.

Distinguishing Quantum Phases through Cusps in Full Counting Statistics.

Measuring physical observables requires averaging experimental outcomes over numerous identical measurements. The complete distribution function of possible outcomes or its Fourier transform, known as the full counting statistics, provides a more detailed description. This method captures the fundamental quantum fluctuations in many-body systems and has gained significant attention in quantum transport research. In this Letter, we propose that cusp singularities in the full counting statistics are a novel tool for distinguishing between ordered and disordered phases. As a specific example, we focus on the superfluid-to-Mott transition in the Bose-Hubbard model. Through both analytical analysis and numerical simulations, we demonstrate that the full counting statistics exhibit a cusp singularity as a function of the phase angle in the superfluid phase when the subsystem size is sufficiently large, while it remains smooth in the Mott phase. This discontinuity can be interpreted as a first-order transition between different semiclassical configurations of vortices. We anticipate that our discoveries can be readily tested using state-of-the-art ultracold atom and superconducting qubit platforms.

MCNN_MC: Computational Prediction of Mitochondrial Carriers and Investigation of Bongkrekic Acid Toxicity Using Protein Language Models and Convolutional Neural Networks.

Mitochondrial carriers (MCs) are essential proteins that transport metabolites across mitochondrial membranes and play a critical role in cellular metabolism. ADP/ATP (adenosine diphosphate/adenosine triphosphate) is one of the most important carriers as it contributes to cellular energy production and is susceptible to the powerful toxin bongkrekic acid. This toxin has claimed several lives; for example, a recent foodborne outbreak in Taipei, Taiwan, has caused four deaths and sickened 30 people. The issue of bongkrekic acid poisoning has been a long-standing problem in Indonesia, with reports as early as 1895 detailing numerous deaths from contaminated coconut fermented cakes. In bioinformatics, significant advances have been made in understanding biological processes through computational methods; however, no established computational method has been developed for identifying mitochondrial carriers. We propose a computational bioinformatics approach for predicting MCs from a broader class of secondary active transporters with a focus on the ADP/ATP carrier and its interaction with bongkrekic acid. The proposed model combines protein language models (PLMs) with multiwindow scanning convolutional neural networks (mCNNs). While PLM embeddings capture contextual information within proteins, mCNN scans multiple windows to identify potential binding sites and extract local features. Our results show 96.66% sensitivity, 95.76% specificity, 96.12% accuracy, 91.83% Matthews correlation coefficient (MCC), 94.63% F1-Score, and 98.55% area under the curve (AUC). The results demonstrate the effectiveness of the proposed approach in predicting MCs and elucidating their functions, particularly in the context of bongkrekic acid toxicity. This study presents a valuable approach for identifying novel mitochondrial complexes, characterizing their functional roles, and understanding mitochondrial toxicology mechanisms. Our findings, that utilize computational methods to improve our understanding of cellular processes and drug-target interactions, contribute to the development of therapeutic strategies for mitochondrial disorders, reducing the devastating effects of bongkrekic acid poisoning.

Unraveling the mediation role of frailty and depression in the relationship between social support and self-management among Chinese elderly COPD patients: a cross-sectional study.

BACKGROUND: Self-management (SM) is the key factor in controlling the progression of chronic obstructive pulmonary disease (COPD). Previous studies have reported that majority of COPD patients later presented with frailty and mental health diseases, which affect self-management. This study attempted to explore the mediation role of depression and frailty between social support and self-management in elderly COPD population. METHODS: Six hundred twenty-seven stable elderly COPD patients admitted to 5 public hospitals in Ningxia, China were selected as study subjects by convenience sampling method. Self-management, frailty, depression and social support were assessed using the COPD Self-management Scale (COPD-SMS), Frail Scale (FS), 15-item Geriatric Depression Scale (GDS-15), and Social Support Rating Scale (SSRS) respectively. The Pearson correlation analysis was used to assess the correlation between variables. Additionally, SPSS25.0 PROCESS plugin Model 6 was used to explore the mediating effects of frailty and depression in the relationship between social support and self-management. RESULTS: The mean participant age was 72.87 ± 7.03 years, 60.4% of participants were male. The mean total score of the COPD-SMS was 156.99 ± 25.15. Scores for the SSRS, FS, and GDS-15 were significantly correlated with COPD-SMS (p < 0.05). The analysis of the mediation effect demonstrated that social support has a direct predictive effect on self- management (ß = 1.687, 95%CI: 1.359 to 2.318). Additionally, social support can also predict self- management indirectly through the mediation of depression (ß = 0.290, 95%CI: 0.161 to 0.436) and frailty-depression (ß = 0.040, 95%CI: 0.010 to 0.081). However, the mediation effect of frailty alone was not found to be statistically significant (ß =-0.010, 95%CI: -0.061 to 0.036). The direct effect accounted for 84.06% of the total effect, while the indirect effect accounted for 15.94% of the total effect. CONCLUSION: Self-management among elderly COPD patients was relatively moderate to low. Furthermore, frailty and depression were found to have a partially mediation role in the relationship between social support and self-management. Therefore, healthcare professionals need to comprehensively consider the frailty and depression status of patients, and implement targeted intervention measures as part of their care, which can improve the self-management of elderly COPD patients.

The role of nutrition in analysis of risk factors and short-term outcomes for late-onset necrotizing enterocolitis among very preterm infants: a nationwide, multicenter study in China.

BACKGROUND: Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease, primarily affects preterm newborns and occurs after 7 days of life (late-onset NEC, LO-NEC). Unfortunately, over the past several decades, not much progress has been made in its treatment or prevention. This study aimed to analyze the risk factors for LO-NEC, and the impact of LO-NEC on short-term outcomes in very preterm infants (VPIs) with a focus on nutrition and different onset times. METHOD: Clinical data of VPIs were retrospectively collected from 28 hospitals in seven different regions of China from September 2019 to December 2020. A total of 2509 enrolled VPIs were divided into 2 groups: the LO-NEC group and non-LO-NEC group. The LO-NEC group was divided into 2 subgroups based on the onset time: LO-NEC occurring between 8 ~ 14d group and LO-NEC occurring after 14d group. Clinical characteristics, nutritional status, and the short-term clinical outcomes were analyzed and compared among these groups. RESULTS: Compared with the non-LO-NEC group, the LO-NEC group had a higher proportion of anemia, blood transfusion, and invasive mechanical ventilation (IMV) treatments before NEC; the LO-NEC group infants had a longer fasting time, required longer duration to achieve the target total caloric intake (110 kcal/kg) and regain birthweight, and showed slower weight growth velocity; the cumulative dose of the medium-chain and long-chain triglyceride (MCT/LCT) emulsion intake in the first week after birth was higher and breastfeeding rate was lower. Additionally, similar results including a higher proportion of IMV, lower breastfeeding rate, more MCT/LCT emulsion intake, slower growth velocity were also found in the LO-NEC group occurring between 8 ~ 14d when compared to the LO-NEC group occurring after 14 d (all (P < 0.05). After adjustment for the confounding factors, high proportion of breastfeeding were identified as protective factors and long fasting time before NEC were identified as risk factors for LO-NEC; early feeding were identified as protective factors and low gestational age, grade III ~ IV neonatal respiratory distress syndrome (NRDS), high accumulation of the MCT/LCT emulsion in the first week were identified as risk factors for LO-NEC occurring between 8 ~ 14d. Logistic regression analysis showed that LO-NEC was a risk factor for late-onset sepsis, parenteral nutrition-associated cholestasis, metabolic bone disease of prematurity, and extrauterine growth retardation. CONCLUSION: Actively preventing premature birth, standardizing the treatment of grade III ~ IV NRDS, and optimizing enteral and parenteral nutrition strategies may help reduce the risk of LO-NEC, especially those occurring between 8 ~ 14d, which may further ameliorate the short-term clinical outcome of VPIs. TRIAL REGISTRATION: ChiCTR1900023418 (26/05/2019).

A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer.

Cellular metabolism in cancer is significantly altered to support the uncontrolled tumor growth. How metabolic alterations contribute to hormonal therapy resistance and disease progression in prostate cancer (PCa) remains poorly understood. Here we report a glutaminase isoform switch mechanism that mediates the initial therapeutic effect but eventual failure of hormonal therapy of PCa. Androgen deprivation therapy inhibits the expression of kidney-type glutaminase (KGA), a splicing isoform of glutaminase 1 (GLS1) up-regulated by androgen receptor (AR), to achieve therapeutic effect by suppressing glutaminolysis. Eventually the tumor cells switch to the expression of glutaminase C (GAC), an androgen-independent GLS1 isoform with more potent enzymatic activity, under the androgen-deprived condition. This switch leads to increased glutamine utilization, hyperproliferation, and aggressive behavior of tumor cells. Pharmacological inhibition or RNA interference of GAC shows better treatment effect for castration-resistant PCa than for hormone-sensitive PCa in vitro and in vivo. In summary, we have identified a metabolic function of AR action in PCa and discovered that the GLS1 isoform switch is one of the key mechanisms in therapeutic resistance and disease progression.

Measuring Human Auditory Evoked Fields with a Flexible Multi-Channel OPM-Based MEG System.

BACKGROUND: Magnetoencephalography (MEG) is a non-invasive imaging technique for directly measuring the external magnetic field generated from synchronously activated pyramidal neurons in the brain. The optically pumped magnetometer (OPM) is known for its less expensive, non-cryogenic, movable and user-friendly custom-design provides the potential for a change in functional neuroimaging based on MEG. METHODS: An array of OPMs covering the opposite sides of a subject's head is placed inside a magnetically shielded room (MSR) and responses evoked from the auditory cortices are measured. RESULTS: High signal-to-noise ratio auditory evoked response fields (AEFs) were detected by a wearable OPM-MEG system in a MSR, for which a flexible helmet was specially designed to minimize the sensor-to-head distance, along with a set of bi-planar coils developed for background field and gradient nulling. Neuronal current sources activated in AEF experiments were localized and the auditory cortices showed the highest activities. Performance of the hybrid optically pumped magnetometer-magnetoencephalography/electroencephalography (OPM-MEG/EEG) system was also assessed. CONCLUSIONS: The multi-channel OPM-MEG system performs well in a custom built MSR equipped with bi-planar coils and detects human AEFs with a flexible helmet. Moreover, the similarities and differences of auditory evoked potentials (AEPs) and AEFs are discussed, while the operation of OPM-MEG sensors in conjunction with EEG electrodes provides an encouraging combination for the exploration of hybrid OPM-MEG/EEG systems.

Single-Cell Transcriptomics Reveals Early Effects of Ionizing Radiation on Bone Marrow Mononuclear Cells in Mice.

Ionizing radiation exposure can cause damage to diverse tissues and organs, with the hematopoietic system being the most sensitive. However, limited information is available regarding the radiosensitivity of various hematopoietic cell populations in the bone marrow due to the high heterogeneity of the hematopoietic system. In this study, we observed that granulocyte-macrophage progenitors, hematopoietic stem/progenitor cells, and B cells within the bone marrow showed the highest sensitivity, exhibiting a rapid decrease in cell numbers following irradiation. Nonetheless, neutrophils, natural killer (NK) cells, T cells, and dendritic cells demonstrated a certain degree of radioresistance, with neutrophils exhibiting the most pronounced resistance. By employing single-cell transcriptome sequencing, we investigated the early responsive genes in various cell types following irradiation, revealing that distinct gene expression profiles emerged between radiosensitive and radioresistant cells. In B cells, radiation exposure led to a specific upregulation of genes associated with mitochondrial respiratory chain complexes, suggesting a connection between these complexes and cell radiosensitivity. In neutrophils, radiation exposure resulted in fewer gene alterations, indicating their potential for distinct mechanisms in radiation resistance. Collectively, this study provides insights into the molecular mechanism for the heterogeneity of radiosensitivity among the various bone marrow hematopoietic cell populations.

Dissolved trace elements in the Ganges-Brahmaputra-Meghna River Basin: A new approach for estimating trace element flux inputs from rivers into the world's oceans.

Understanding the changes in the chemical compositions of dissolved trace elements from source to sink is important for determining their spatiotemporal variations and the contributions from each sub-catchment in the Ganges, Brahmaputra, and Meghna Rivers. To estimate weathering and matter transfer in these Rivers and the Ganges-Brahmaputra-Meghna (G-B-M) Estuary, we measured 15 dissolved trace element concentrations from surface and bottom water samples and exchangeable trace metals from suspended particulate matter (SPM). From December 2019 to January 2020, post-monsoon samples were collected from the upstream of the three rivers and the G-B-M Estuary. Dissolved trace elements in the Ganges and Meghna Rivers exhibited remarkable spatial variations, whereas those in the Brahmaputra River and the G-B-M Estuary were uniform. The dissolved trace elements, basic information (river length and drainage area), and physicochemical parameters (pH, dissolved oxygen, and conductivity) of the three rivers were inconsistent. The sample sites near urban areas and industrial centers had high concentrations of dissolved trace elements. In the G-B-M Estuary, iron and lead concentrations decreased along the salinity gradient, whereas selenium levels gradually increased, which may have been released by the SPM owing to its highly exchangeable trace metals. Compared with historical concentrations, trace elements that entered the G-B Estuary from the Ganges and Brahmaputra Rivers exhibited either decreased or increased metal fluxes due to additional terrigenous sources, suggesting that the inputs of trace element flux from the Ganges and Brahmaputra Rivers into the oceans may need to be re-evaluated. Furthermore, Fe and Pb concentrations and river fluxes in the Ganges and Changjiang have decreased in recent years. Hence, the fluxes of certain trace elements that enter the oceans from large rivers may require re-evaluation.

Integrating proximal soil sensing data and environmental variables to enhance the prediction accuracy for soil salinity and sodicity in a region of Xinjiang Province, China.

Soil salinization and sodification, the primary causes of land degradation and desertification in arid and semi-arid regions, demand effective monitoring for sustainable land management. This study explores the utility of partial least square (PLS) latent variables (LVs) derived from visible and near-infrared (Vis-NIR) spectroscopy, combined with remote sensing (RS) and auxiliary variables, to predict electrical conductivity (EC) and sodium absorption ratio (SAR) in northern Xinjiang, China. Using 90 soil samples from the Karamay district, machine learning models (Random Forest, Support Vector Regression, Cubist) were tested in four scenarios. Modeling results showed that RS and Land use alone were unreliable predictors, but the addition of topographic attributes significantly improved the prediction accuracy for both EC and SAR. The incorporation of PLS LVs derived from Vis-NIR spectroscopy led to the highest performance by the Random Forest model for EC (CCC = 0.83, R2 = 0.80, nRMSE = 0.48, RPD = 2.12) and SAR (CCC = 0.78, R2 = 0.74, nRMSE = 0.58, RPD = 2.25). The variable importance analysis identified PLS LVs, certain topographic attributes (e.g., valley depth, elevation, channel network base level, diffuse insolation), and specific RS data (i.e., polarization index of VV + VH) as the most influential predictors in the study area. This study affirms the efficiency of Vis-NIR data for digital soil mapping, offering a cost-effective solution. In conclusion, the integration of proximal soil sensing techniques and highly relevant topographic attributes with the RF model has the potential to yield a reliable spatial model for mapping soil EC and SAR. This integrated approach allows for the delineation of hazardous zones, which in turn enables the consideration of best management practices and contributes to the reduction of the risk of degradation in salt-affected and sodicity-affected soils.

UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies.

Legubicin, a novel prodrug based on doxorubicin, has both albumin-binding and legumain-activating properties. The aim of this study was to develop and validate a UHPLC-MS/MS method for investigating the in vivo pharmacokinetics and tissue distribution profiles of legubicin in rats and tumor-bearing mice following intravenous administration, and to compare this prodrug with the positive control drug doxorubicin. The study employed a UHLC-MS/MS method to determine the levels of albumin-bound of legubicin and two metabolites (free Leu-DOX and DOX) in plasma, tumor, and tissue samples. This method was validated for good selectivity, high sensitivity, excellent extraction recovery, and short run time. The results showed that legubicin was present in the circulation in vivo mainly in a protein-bound form with larger AUC values and lower clearance and distribution, and essentially released small amounts of doxorubicin. Compared to administration of equimolar doses of doxorubicin, legubicin showed increased exposure of the active drug in the tumor and decreased the level of the active drug in the heart and kidney. This study provides valuable information on the pharmacokinetics and tissue distribution of legubicin, implicating its potential as a novel and effective drug candidate for anti-cancer therapies.

AMPK activation attenuates central sensitization in a recurrent nitroglycerin-induced chronic migraine mouse model by promoting microglial M2-type polarization.

BACKGROUND: Energy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM. METHODS: Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention. RESULTS: Repeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1ß, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway. CONCLUSIONS: AMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine.