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Abstract Lawsonia intracellularis is the causative agent of proliferative enteropathy. While it harbors genes encoding the entire apparatus required for the type III secretion system (T3SS) and the expression of some of these components has been detected during experimental infection, the identification of L. intracellularis T3SS substrates (effector proteins) has been hampered. The Yersinia T3SS and yeast growth inhibition assays are two important heterologous systems used for the characterization of effector proteins. Bacterial EPIYA effectors are a distinct class of bacterial effectors defined by the presence of EPIYA or the EPIYA-related motif. When delivered into host cells via a T3SS or type IV secretion system, these effectors undergo tyrosine phosphorylation of the EPIYA motif, which enables them to manipulate host cell signaling by promiscuously interacting with multiple SH2 domain-containing proteins. A previous study showed that L. intracellularis LI0666 contains two EPIYA motifs and speculated that this protein could be a T3SS effector. In this study, we show that LI0666 is secreted by Yersinia in a T3SS-dependent manner and inhibits yeast growth. LI0666 is phosphorylated at tyrosine residues in porcine intestinal epithelial cells and in human epithelial cells. Like the archetypal EPIYA effector CagA, the EPIYA-containing region is not required for LI0666 association with yeast and mammalian cell membranes. Our results indicate that LI0666 is an authentic bacterial EPIYA effector. Identification of the tyrosine kinases that are responsible for LI0666 phosphorylation and the SH2 domain-containing host proteins that LI0666 interacts with will help to explore the molecular mechanisms of LI0666 in disease development.

Abstract Background In modern animal husbandry, breeders pay increasing attention to improving sow nutrition during pregnancy and lactation to favor the health of neonates. Sow milk is a main food source for piglets during their first three weeks of life, which is not only a rich repository of essential nutrients and a broad range of bioactive compounds, but also an indispensable source of commensal bacteria. Maternal milk microorganisms are important sources of commensal bacteria for the neonatal gut. Bacteria from maternal milk may confer a health benefit on the host. Methods Sow milk bacteria were isolated using culturomics followed by identification using 16S rRNA gene sequencing. To screen isolates for potential probiotic activity, the functional evaluation was conducted to assess their antagonistic activity against pathogens in vitro and evaluate their resistance against oxidative stress in damaged Drosophila induced by paraquat. In a piglet feeding trial, a total of 54 newborn suckling piglets were chosen from nine sows and randomly assigned to three treatments with different concentrations of a candidate strain. Multiple approaches were carried out to verify its antioxidant function including western blotting, enzyme activity analysis, metabolomics and 16S rRNA gene amplicon sequencing. Results The 1240 isolates were screened out from the sow milk microbiota and grouped into 271 bacterial taxa based on a nonredundant set of 16S rRNA gene sequencing. Among 80 Pediococcus isolates, a new Pediococcus pentosaceus strain (SMM914) showed the best performance in inhibition ability against swine pathogens and in a Drosophila model challenged by paraquat. Pretreatment of piglets with SMM914 induced the Nrf2-Keap1 antioxidant signaling pathway and greatly affected the pathways of amino acid metabolism and lipid metabolism in plasma. In the colon, the relative abundance of Lactobacillus was significantly increased in the high dose SMM914 group compared with the control group. Conclusion P. pentosaceus SMM914 is a promising probiotic conferring antioxidant capacity by activating the Nrf2-Keap1 antioxidant signaling pathway in piglets. Our study provided useful resources for better understanding the relationships between the maternal microbiota and offspring. Video Abstract

The efficacy of acupuncture and moxibustion in the treatment of depression has been fully recognized internationally. However, its central mechanism is still not developed into a unified standard, and it is generally believed that the central mechanism is regulation of the cortical striatum thalamic neural pathway of the limbic system. In recent years, some scholars have applied functional magnetic resonance imaging (fMRI) to study the central mechanism and the associated brain effects of acupuncture and moxibustion treatment for depression. This study reviews the acupuncture and moxibustion treatment of depression from two aspects: (1) fMRI study of the brain function related to the acupuncture treatment of depression: different acupuncture and moxibustion methods are summarized, the fMRI technique is elaborately explained, and the results of fMRI study of the effects of acupuncture are analyzed in detail, and (2) fMRI associated “brain functional network” effects of acupuncture and moxibustion on depression, including the effects on the hippocampus, the amygdala, the cingulate gyrus, the frontal lobe, the temporal lobe, and other brain regions. The study of the effects of acupuncture on brain imaging is not adequately developed and still needs further improvement and development. The brain function networks associated with the acupuncture treatment of depression have not yet been adequately developed to provide a scientific and standardized mechanism of the effects of acupuncture. For this purpose, this study analyzes in-depth the clinical studies on the treatment of anxiety and depression by acupuncture and moxibustion, by depicting how the employment of fMRI technology provides significant imaging changes in the brain regions. Therefore, the study also provides a reference for future clinical research on the treatment of anxiety and depression.

ABSTRACT Gut microbes can affect host adaptation to various environment conditions. Escherichia coli is a common gut species, including pathogenic strains and nonpathogenic strains. This study was conducted to investigate the effects of different E. coli strains in the gut on the health of pigs. In this study, the complete genomes of two E. coli strains isolated from pigs were sequenced. The whole genomes of Y18J and the enterotoxigenic E. coli strain W25K were compared to determine their roles in pig adaptation to disease. Y18J was isolated from feces of healthy piglets and showed strong antimicrobial activity against W25K in vitro. Gene knockout experiments and complementation analysis followed by modeling the microbe-microbe interactions demonstrated that the antagonistic mechanism of Y18J against W25K relied on the bacteriocins colicin B and colicin M. Compared to W25K, Y18J is devoid of exotoxin-coding genes and has more secondary-metabolite-biosynthetic gene clusters. W25K carries more genes involved in genome replication, in accordance with a shorter cell cycle observed during a growth experiment. The analysis of gut metagenomes in different pig breeds showed that colicins B and M were enriched in Laiwu pigs, a Chinese local breed, but were scarce in boars and Duroc pigs. IMPORTANCE This study revealed the heterogeneity of E. coli strains from pigs, including two strains studied by both in silico and wet experiments in detail and 14 strains studied by bioinformatics analysis. E. coli Y18J may improve the adaptability of pigs toward disease resistance through the production of colicins B and M. Our findings could shed light on the pathogenic and harmless roles of E. coli in modern animal husbandry, leading to a better understanding of intestinal-microbe–pathogen interactions in the course of evolution.

Glial cell-line-derived neurotrophic factor (GDNF) is a potent neuroprotective agent in cellular and animal models of Parkinson’s disease (PD). However, CNS delivery of GDNF in clinical trials has proven challenging due to blood-brain barrier (BBB) impermeability, poor diffusion within brain tissue, and large brain size. We report that using non-toxic mobilization-enabled preconditioning, hematopoietic stem cell (HSC) transplantation-based macrophage-mediated gene delivery may provide a solution to overcome these obstacles. Syngeneic bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into 14-week-old MitoPark mice exhibiting PD-like impairments. Transplant preconditioning with granulocyte colony-stimulating factor (G-CSF) and AMD3100 was used to vacate bone marrow stem cell niches. Chimerism reached ∼80% after seven transplantation cycles. Transgene-expressing macrophages infiltrated degenerating CNS regions of MitoPark mice (not wild-type littermate controls), resulting in increased GDNF levels in the midbrain. Macrophage GDNF delivery not only markedly improved motor and non-motor dysfunction, but also dramatically mitigated the loss of dopaminergic neurons in both substantia nigra and the ventral tegmental area and preserved axonal terminals in the striatum. Striatal dopamine levels were almost completely restored. Our data support further development of mobilization-enabled HSC transplantation (HSCT)-based macrophage-mediated GDNF gene delivery as a disease-modifying therapy for PD.

Weaning of piglets could increase the risk of infecting with Gram-negative pathogens, which can further bring about a wide array of virulence factors including the endotoxin lipopolysaccharide (LPS). It is in common practice that the use of antibiotics has been restricted in animal husbandry. Alkaline phosphatase (AKP) plays an important role in the detoxification and anti-inflammatory effects of LPS. This study investigated the protective effects of AKP on intestinal epithelial cells during inflammation. Site-directed mutagenesis was performed to modulate the AKP activity. The enzyme activity tests showed that the activity of the DelSigD153G-D330N mutants in B. subtilis was nearly 1,600 times higher than that of the wild-type AKP. In this study, an in vitro LPS-induced inflammation model using IPEC-J2 cells was established. The mRNA expression of interleukin-(IL-) 6, IL-8, and tumor necrosis factor-α (TNF-α) were extremely significantly downregulated, and that of ASC amino acid transporter 2 (ASCT-2), zonula occludens protein-1 (ZO-1), and occludin-3 (CLDN-3) were significantly upregulated by the DelSigD153G-D330N mutant compared with LPS treatment. This concludes the anti-inflammatory role of AKP on epithelial membrane, and we are hopeful that this research could achieve a sustainable development for the pig industry.

Online end-to-end electroencephalogram (EEG) classification with high performance can assess the brain status of patients with Major Depression Disabled (MDD) and track their development status in time with minimizing the risk of falling into danger and suicide. However, it remains a grand research challenge due to (1) the embedded intensive noises and the intrinsic non-stationarity determined by the evolution of brain states, (2) the lack of effective decoupling of the complex relationship between neural network and brain state during the attack of brain diseases. This study designs a Frequency Channel-based convolutional neural network (CNN), namely FCCNN, to accurately and quickly identify depression, which fuses the brain rhythm to the attention mechanism of the classifier with aiming at focusing the most important parts of data and improving the classification performance. Furthermore, to understand the complexity of the classifier, this study proposes a calculation method of information entropy based on the affinity propagation (AP) clustering partition to measure the complexity of the classifier acting on each channel or brain region. We perform experiments on depression evaluation to identify healthy and MDD. Results report that the proposed solution can identify MDD with an accuracy of 99±0.08%, the sensitivity of 99.07±0.05%, and specificity of 98.90±0.14%. Furthermore, the experiments on the quantitative interpretation of FCCNN illustrate significant differences between the frontal, left, and right temporal lobes of depression patients and the healthy control group.

Trace minerals are extremely important for balanced nutrition, growth, and development in animals and humans. Phytic acid chelation promotes the use of probiotics in nutrition. The phytic acid-degrading strain Lactococcus lactis psm16 was obtained from swine milk by enrichment culture and direct plate methods. In this study, we evaluated the effect of the strain psm16 on mineral element content in a mouse model. Mice were divided into four groups: basal diet, 1% phytic acid, 1% phytic acid + psm16, 1% phytic acid + 500 U/kg commercial phytase. Concentrations of acetic acid, propionic acid, butyric acid, and total short-chain fatty acids were significantly increased in the strain psm16 group compared to the phytic acid group. The concentrations of copper (p = 0.021) and zinc (p = 0.017) in liver, calcium (p = 0.000), manganese (p = 0.000), and zinc (p = 0.000) in plasma and manganese (p = 0.010) and zinc (p = 0.022) in kidney were significantly increased in psm16 group, while copper (p = 0.007) and magnesium (p = 0.001) were significantly reduced. In conclusion, the addition of phytic acid-degrading bacteria psm16 into a diet including phytic acid can affect the content of trace elements in the liver, kidney, and plasma of mice, counteracting the harmful effects of phytic acid.

Endophytes represent a ubiquitous and magical world in plants. Almost all plant species studied by different researchers have been found to harbor one or more endophytes, which protect host plants from pathogen invasion and from adverse environmental conditions. They produce various metabolites that can directly inhibit the growth of pathogens and even promote the growth and development of the host plants. In this review, we focus on the biological control of plant diseases, aiming to elucidate the contribution and key roles of endophytes and their metabolites in this field with the latest research information. Metabolites synthesized by endophytes are part of plant disease management, and the application of endophyte metabolites to induce plant resistance is very promising. Furthermore, multi-omics should be more fully utilized in plant–microbe research, especially in mining novel bioactive metabolites. We believe that the utilization of endophytes and their metabolites for plant disease management is a meaningful and promising research direction that can lead to new breakthroughs in the development of more effective and ecosystem-friendly insecticides and fungicides in modern agriculture.

The MitoPark mouse, a relatively new genetic model of Parkinson's disease (PD), has a dopaminergic neuron-specific knock-out that inactivates the mitochondrial transcription factor A (Tfam), a protein essential for mitochondrial DNA expression and maintenance. This study used multimodal MRI to characterize the neuroanatomical correlates of PD-related deficits in MitoPark mice, along with functional behavioral tests. Compared with age-matched wild-type animals, MitoPark mice at 30 weeks showed: i) reduced whole-brain volume and increased ventricular volume, indicative of brain atrophy, ii) reduced transverse relaxation time (T2*) of the substantia nigra and striatum, suggestive of abnormal iron accumulation, iii) reduced apparent diffusion coefficient in the substantia nigra, suggestive of neuronal loss, iv) reduced fractional anisotropy in the corpus callosum and substantia nigra, indicative of white-matter damages, v) cerebral blood flow was not significantly affected, and vi) reduced motor activity in open-field tests, reduced memory in novel object recognition tests, as well as decreased mobility in tail suspension tests, an indication of depression. In sum, MitoPark mice recapitulate changes in many MRI parameters reported in PD patients. Multimodal MRI may prove useful for evaluating neuroanatomical correlates of PD pathophysiology in MitoPark mice, and for longitudinally monitoring disease progression and therapeutic interventions for PD.

Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by progressive loss of dopamine neurons, leading to loss of motor coordination. However, PD is associated with a high rate of non-motor neuropsychiatric comorbities that often develop before the onset of movement symptoms. The MitoPark transgenic mouse model is the first to recapitulate the cardinal clinical features, namely progressive neurodegeneration and death of neurons, loss of motor function and therapeutic response to L-DOPA. To investigate whether MitoPark mice exhibit early onset of cognitive impairment, a non-motor neuropsychiatric comorbidity, we measured performance on a spatial learning and memory task before (∼8 weeks) or after (∼20 weeks) the onset of locomotor decline in MitoPark mice or in littermate controls. Consistent with previous studies, we established that a progressive loss of spontaneous locomotor activity began at 12 weeks of age, which was followed by progressive loss of body weight beginning at 16-20 weeks. Spatial learning and memory was measured using the Barnes Maze. By 20 weeks of age, MitoPark mice displayed a substantial reduction in overall locomotor activity that impaired their ability to perform the task. However, in the 8-week-old mice, locomotor activity was no different between genotypes, yet MitoPark mice took longer, traveled further and committed more errors than same age control mice, while learning to successfully navigate the maze. The modest between-day learning deficit of MitoPark mice was characterized by impaired within-day learning during the first two days of testing. No difference was observed between genotypes during probe trials conducted one or twelve days after the final acquisition test. Additionally, 8-week-old MitoPark mice exhibited impaired novel object recognition when compared to control mice. Together, these data establish that mild cognitive impairment precedes the loss of motor function in a novel rodent model of PD, which may provide unique opportunities for therapeutic development.

Abstract Background Substance P (SP), which mainly exists in a subtype of small-diameter dorsal root ganglion (DRG) neurons, is an important signal molecule in pain processing in the spinal cord. Our previous results have proved the expression of SP receptor neurokinin-1 (NK-1) on DRG neurons and its interaction with transient receptor potential vanilloid 1 (TRPV1) receptor. Results In this study we investigated the effect of NK-1 receptor agonist on Nav1.8, a tetrodotoxin (TTX)-resistant sodium channel, in rat small-diameter DRG neurons employing whole-cell patch clamp recordings. NK-1 agonist [Sar9, Met(O2)11]-substance P (Sar-SP) significantly enhanced the Nav1.8 currents in a subgroup of small-diameter DRG neurons under both the normal and inflammatory situation, and the enhancement was blocked by NK-1 antagonist Win51708 and protein kinase C (PKC) inhibitor bisindolylmaleimide (BIM), but not the protein kinase A (PKA) inhibitor H89. In particular, the inhibitor of PKCε, a PKC isoform, completely blocked this effect. Under current clamp model, Sar-SP reduced the amount of current required to evoke action potentials and increased the firing rate in a subgroup of DRG neurons. Conclusion These data suggest that activation of NK-1 receptor potentiates Nav1.8 sodium current via PKCε-dependent signaling pathway, probably participating in the generation of inflammatory hyperalgesia.

Lysosomes are essential degradative organelles and signaling hubs within cells, playing a crucial role in the regulation of macroautophagy/autophagy. Dysfunction of lysosomes and impaired autophagy are closely associated with the development of various neurodegenerative diseases. Enhancing lysosomal activity and boosting autophagy levels holds great promise as effective strategies for treating these diseases. However, there remains a lack of methods to dynamically regulate lysosomal activity and autophagy levels in living cells or animals. In our recent work, we applied optogenetics to manipulate lysosomal physiology and function, developing three lysosome-targeted optogenetic tools: lyso-NpHR3.0, lyso-ArchT, and lyso-ChR2. These new actuators enable light-dependent regulation of key aspects such as lysosomal membrane potential, lumenal pH, hydrolase activity, degradation processes, and Ca 2+ dynamics in living cells. Notably, lyso-ChR2 activation induces autophagy via the MTOR pathway while it promotes Aβ clearance through autophagy induction in cellular models of Alzheimer disease. Furthermore, lyso-ChR2 activation reduces Aβ deposition and alleviates Aβ-induced paralysis in Caenorhabditis elegans models of Alzheimer disease. Our lysosomal optogenetic actuators offer a novel method for dynamically regulating lysosomal physiology and autophagic activity in living cells and animals.

The density of wood is a key indicator of the carbon investment strategies of trees, impacting productivity and carbon storage. Despite its importance, the global variation in wood density and its environmental controls remain poorly understood, preventing accurate predictions of global forest carbon stocks. Here we analyse information from 1.1 million forest inventory plots alongside wood density data from 10,703 tree species to create a spatially explicit understanding of the global wood density distribution and its drivers. Our findings reveal a pronounced latitudinal gradient, with wood in tropical forests being up to 30% denser than that in boreal forests. In both angiosperms and gymnosperms, hydrothermal conditions represented by annual mean temperature and soil moisture emerged as the primary factors influencing the variation in wood density globally. This indicates similar environmental filters and evolutionary adaptations among distinct plant groups, underscoring the essential role of abiotic factors in determining wood density in forest ecosystems. Additionally, our study highlights the prominent role of disturbance, such as human modification and fire risk, in influencing wood density at more local scales. Factoring in the spatial variation of wood density notably changes the estimates of forest carbon stocks, leading to differences of up to 21% within biomes. Therefore, our research contributes to a deeper understanding of terrestrial biomass distribution and how environmental changes and disturbances impact forest ecosystems., (© 2024. The Author(s).)

Against the backdrop of global warming, the pollutants that were once "temporarily stored" in the permafrost are gradually being released, posing significant impacts on the environment. This has become an internationally focused hot topic. In this study, the contents of 11 elements such as As, Ti, Cd, Cr, Co, Mn, Cu, Pb, Ni, Zn and V in soil samples from 128 sampling points in the freeze-thaw area of the Tuotuo River in the source region of the Yangtze River on the Qinghai-Tibet Plateau were determined to evaluate the possible sources, contamination status and ecological, environmental and health risks of these elements. The mean values of As, Cd, Pb and Zn were higher than the corresponding Tibet soil background values. Among fourteen PTEs, As, Cd and Pb had the highest average values of enrichment factor and pollution index, indicating that freeze-thaw area soils showed moderate enrichment and pollution with As, Cd and Pb. Mean ecological risk factor (ER) of Cd was 109 and other PTEs mean ER values < 40, whereas ecological risk index (RI) values of all PTEs ranged from 59.5 to 880 and mean RI values was 152, indicating moderate ecological risk in study area. Explanatory power q value of total S (TS) content was 0.217 by GeogDetector, indicating TS was the most significant contributing factor to RI. Correlation analysis and PCA analysis showed that Cr, Cu, Ni, Co, Mn, Ti, V were mainly originated from natural sources, Cd, Pb and Zn from traffic activity, As from long-distance migration-freeze-thaw., (© 2024. The Author(s).)

The early diagnosis of hepatocellular carcinomas (HCCs) remains challenging in the clinic. Primovist-enhanced magnetic resonance imaging (MRI) aids HCC diagnosis but loses sensitivity for tumors <2 cm. Therefore, developing advanced MRI contrast agents is imperative for improving the diagnostic accuracy of HCCs in very-early-stage. To address this challenge, PEGylated ultra-small iron oxide nanoparticles (PUSIONPs) are synthesized and employed as liver-specific T1 MRI contrast agents. Intravenous delivery produces simultaneous hyperintense HCC and hypointense hepatic parenchyma signals on T1 imaging, creating an extraordinarily high tumor-to-liver contrast. Systematic studies uncover PUSIONP distribution in hepatic parenchyma, HCC lesions at the organ, tissue, cellular, and subcellular levels, revealing endosomal confinement of PUSIONP without aggregation. By mimicking such situations, the dependency of relaxometric properties on local PUSIONP concentration is investigated, emphasizing the key role of different endosomal concentrations in liver and tumor cells for high tumor-to-liver contrast and clear tumor boundaries. These findings offer exceptional imaging capabilities for early HCC diagnosis, potentially benefiting real HCC patients., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The PEGylated ultrasmall iron oxide nanoparticles (PUSIONPs) exhibit longer blood residence time and better biodegradability than conventional gadolinium-based contrast agents (GBCAs), enabling prolonged acquisitions in contrast-enhanced magnetic resonance angiography (CE-MRA) applications. The image quality of CE-MRA is dependent on the contrast agent concentration and the parameters of the pulse sequences. Here, a closed-form mathematical model is demonstrated and validated to automatically optimize the concentration, echo time (TE), repetition time (TR) and flip angle (FA). The pharmacokinetic studies are performed to estimate the dynamic intravascular concentrations within 12 h postinjection, and the adaptive concentration-dependent sequence parameters are determined to achieve optimal signal enhancement during a prolonged measurement window. The presented model is tested on phantom and in vivo rat images acquired from a 3T scanner. Imaging results demonstrate excellent agreement between experimental measurements and theoretical predictions, and the adaptive sequence parameters obtain better signal enhancement than the fixed ones. The low-dose PUSIONPs (0.03 mmol kg -1 and 0.05 mmol kg -1 ) give a comparable signal intensity to the high-dose one (0.10 mmol kg -1 ) within 2 h postinjection. The presented mathematical model provides guidance for the optimization of the concentration and sequence parameters in PUSIONPs-enhanced MRA, and has great potential for further clinical translation., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Ischemic stroke (IS) is a leading cause of adult disability that can severely compromise the quality of life for patients. Accurately predicting the IS functional outcome is crucial for precise risk stratification and effective therapeutic interventions. We developed a predictive model integrating genetic, environmental, and clinical factors using data from 7819 IS patients in the Third China National Stroke Registry. Employing an 80:20 split, we randomly divided the dataset into development and internal validation cohorts. The discrimination and calibration performance of models were evaluated using the area under the receiver operating characteristic curves (AUC) for discrimination and Brier score with calibration curve in the internal validation cohort. We conducted genome-wide association studies (GWAS) in the development cohort, identifying rs11109607 (ANKS1B) as the most significant variant associated with IS functional outcome. We employed principal component analysis to reduce dimensionality on the top 100 significant variants identified by the GWAS, incorporating them as genetic factors in the predictive model. We employed a machine learning algorithm capable of identifying nonlinear relationships to establish predictive models for IS patient functional outcome. The optimal model was the XGBoost model, which outperformed the logistic regression model (AUC 0.818 versus 0.756, P < .05) and significantly improved reclassification efficiency. Our study innovatively incorporated genetic, environmental, and clinical factors for predicting the IS functional outcome in East Asian populations, thereby offering novel insights into IS functional outcome., (© The Author(s) 2024. Published by Oxford University Press.)

The establishment of soil geochemical baseline and heavy metal pollution assessment in the Qinghai-Tibet Plateau is of great significance for guiding environmental management in the high-cold and high-altitude regions. A total of 126 topsoil samples (0-20 cm) were collected and the contents of Cu, Pb, Zn, Ni, Cr, Cd, As and Hg were determined in the Sabaochaqu basin of the Tuotuo River, the source of the Yangtze River, in the Tibetan Plateau. The baseline values of 8 heavy metals were determined by mathematical statistics, iterative 2times standard deviation method, cumulative frequency and reference element standardization, and the soil heavy metal pollution in the study area was assessed by enrichment factor method and pollution index method. The results showed that the average contents of As, Cd, Cr, Cu, Hg, Ni, Pb and Zn were 31.84, 0.29, 66.07, 17.35, 0.021, 27.86, 49.35 and 88.56 mg/kg, respectively. Baseline values were 22.24, 0.217, 64.16, 15.69, 0.0191, 26.46, 34.91, and 68.62 mg/kg, respectively. There is a great difference between the baseline value of soil heavy metals in study area and the Xizang soil background value, especially the baseline value of Cd was 2.68 times of its background value. The results of the pollution evaluation based on the baseline values showed that the 8 heavy metals were slightly enriched, and the overall pollution status was light pollution, and measures should be taken to control and manage them. The research results can provide a reference value for the evaluation of soil heavy metal pollution in the source region of the Yangtze River, and also provide a theoretical basis for the construction of soil heavy metal baseline values in similar high-cold and high-altitude regions., (© 2024. The Author(s).)

DABMA is a chemical molecule optimized from the parent compound ABMA and exhibits broad-spectrum antipathogenic activity by modulating the host's endolysosomal and autophagic pathways. Both DABMA and ABMA inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a cellular assay, which further expands their anti-pathogen spectrum in vitro. However, their precise mechanism of action has not yet been resolved. TMEM175 is a newly characterized endolysosomal channel which plays an essential role in the homeostasis of endosomes and lysosomes as well as organelle fusion. Here, we show that DABMA increases the endosomal TMEM175 current through organelle patch clamping with an EC 50 of 17.9 μm. Depletion of TMEM175 protein significantly decreases the antitoxin activity of DABMA and affects its action on acidic- and Rab7-positive endosomes as well as on endolysosomal trafficking. Thus, TMEM175 is necessary for DABMA's activity and may represent a druggable target for the development of anti-infective drugs. Moreover, DABMA, as an activator of the TMEM175 channel, may be useful for the in-depth characterization of the physiological and pathological roles of this endolysosomal channel., (© 2024 Federation of European Biochemical Societies.)

Human activities in the last century have intensified global nitrogen deposition, resulting in the degradation of ecosystem function and loss of biodiversity worldwide. Nitrogen addition is a crucial method for examining the effects of atmospheric nitrogen deposition on species composition and structure of soil microbiome and biotic community, as exogenous nitrogen inputs can trigger cascading effects on ecosystem functions. In a 6-year experiment, we evaluated the impact of nitrogen addition on soil microbial-plant-insect systems in desert steppes. Our results show that nitrogen addition significantly altered soil microbial composition and ecological function, leading to a decrease in nitrogen-fixing bacteria and an increase in saprophytic fungi. High levels of nitrogen addition increased total plant biomass while decreasing species diversity. Additionally, high nitrogen addition levels suppressed below-ground biomass of gramineae and legumes compared to low nitrogen addition. Nitrogen addition also increased herbivore abundance by altering insect community structure, particularly benefiting chewing pests over sucking pests, thus heightening the risk of biological disasters through trophic cascading effects. Consequently, excessive nitrogen addition may destabilize desert steppe ecosystems by disturbing soil microbial-plant-insect interactions, hindering the maintenance of biotic community diversity and steppe productivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ecological networks experiencing persistent biological invasions may exhibit distinct topological properties, complicating the understanding of how network topology affects disease transmission during invasion-driven community assembly. We developed a trait-based network model to assess the impact of network topology on disease transmission, measured as community- and species-level disease prevalence. We found that trait-based feeding interactions between host species determine the frequency distribution of the niche of co-occurring species in steady-state communities, being either bimodal or multimodal. The width of the growth kernel influences the degree-biomass relationship of species, being either weakly positive or strongly negative. When this relationship is weakly positive, species-level disease prevalence is primarily correlated with biomass. However, when the degree-biomass relationship is strongly negative, species-level disease prevalence is determined by the difference between a host species' in-degree and out-degree closeness centrality. At the community level, disease prevalence is generally amplified by increasing host richness, community biomass, and the standard deviation of interaction generality, while it is diluted by higher network connectance. Our framework verifies the amplification effects of host richness during invasion-driven community assembly and offers valuable insights for estimating disease prevalence based on host network topology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Our objective was to determine the role of acetyl-Hsp90 and its relationship with the NF-κB p65 signaling pathway in CVDs. We investigated the effect of acetyl-Hsp90 on cardiac inflammation and apoptosis after ischemia-reperfusion injury (I/RI). The results showed that the induction of acetyl-Hsp90 occurred in the heart during I/R and in primary cardiomyocytes during oxygen-glucose deprivation/reoxygenation (OGD/R). Moreover, the nonacetylated mutant of Hsp90 (Hsp90-K284R), through the regulation of ATPase activities within its N-terminal domain (NTD), indirectly or directly increases its interaction with NF-κB p65. This led to a reduction in the activation of the NF-κB p65 pathway, thereby attenuating inflammation, apoptosis, and fibrosis, ultimately leading to an improvement in cardiac function. Furthermore, we demonstrated that recombinant human interleukin-37 (rIL-37) exerts a similar cardioprotective effect by reducing acetylation at K284 of Hsp90 after inhibiting the expression of KAT2A., (© 2024. The Author(s).)

Mastomys natalensis and M. coucha are commensal rodent species endemic to Africa. A recent taxonomic revision within Mastomys leaves the parasite–host list of M. natalensis questionable and that of M. coucha incomplete. The current study aimed to develop a better understanding of the ectoparasite diversity associated with the 2 distinct but closely related rodent species and to explore the influence of host and habitat type on ectoparasite infestations. Between 2014 and 2020, 590 rodents were trapped in 3 habitat types (village, agriculture and natural) across a wildlife-human/domestic animal interface. In total 48 epifaunistic species (45 ectoparasitic and 3 predatory) represented by 29 genera from 4 taxonomic groups (fleas, lice, mites and ticks) were recorded. Only 50% of the epifauna were shared between the 2 rodent species, with mites the most speciose taxon in both host species. The abundance of epifaunistic individuals, and also those of mites and fleas, were significantly higher on male M. natalensis , while ticks were significantly higher on reproductively active M. natalensis . For both rodent species, infestations by most epifaunistic taxa (on M. natalensis ) and some taxa (on M. coucha ) were significantly lower in the village as opposed to the less disturbed agricultural and natural habitat types. The study highlights the importance of host life history, even in closely related rodent species, in shaping parasite profiles and a loss of parasite diversity in more extreme anthropogenic habitats.

Although invasive alien species have long been recognized as a major threat to nature and people, until now there has been no comprehensive global review of the status, trends, drivers, impacts, management and governance challenges of biological invasions. The Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) Thematic Assessment Report on Invasive Alien Species and Their Control (hereafter 'IPBES invasive alien species assessment') drew on more than 13,000 scientific publications and reports in 15 languages as well as Indigenous and local knowledge on all taxa, ecosystems and regions across the globe. Therefore, it provides unequivocal evidence of the major and growing threat of invasive alien species alongside ambitious but realistic approaches to manage biological invasions. The extent of the threat and impacts has been recognized by the 143 member states of IPBES who approved the summary for policymakers of this assessment. Here, the authors of the IPBES assessment outline the main findings of the IPBES invasive alien species assessment and highlight the urgency to act now., (© 2024. Springer Nature Limited.)

Despite the implementation of novel therapeutic regimens and extensive research efforts, chemoresistance remains a formidable challenge in the treatment of acute myeloid leukemia (AML). Notably, the involvement of lysosomes in chemoresistance has sparked interest in developing lysosome-targeted therapies to sensitize tumor cells to currently approved chemotherapy or as innovative pharmacological approaches. Moreover, as ion channels on the lysosomal membrane are critical regulators of lysosomal function, they present potential as novel targets for enhancing chemosensitivity. Here, we discovered that the expression of a lysosomal cation channel, namely transient receptor potential mucolipin 1 (TRPML1), was elevated in AML cells. Inhibiting TRPML1 individually does not impact the proliferation and apoptosis of AML cells. Importantly, inhibition of TRPML1 demonstrated the potential to modulate the sensitivity of AML cells to chemotherapeutic agents. Exploration of the underlying mechanisms revealed that suppression of TRPML1 impaired autophagy while concurrently increasing the production of reactive oxygen species (ROS) and ROS-mediated lipid peroxidation (Lipid-ROS) in AML cells. Finally, the knockdown of TRPML1 significantly reduced OCI-AML3 tumor growth following chemotherapy in a mouse model of human leukemia. In summary, targeting TRPML1 represents a promising approach for combination therapy aimed at enhancing chemosensitivity in treating AML., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The authentication of dairy species has great significance for food safety. This study focused on a more rapid method for identifying major dairy species, and specific recombinase polymerase amplification (RPA)-based assays for cattle, goat, sheep, camel and donkey were developed. Through the developed RPA-based assays, goats and sheep could be simultaneously identified and bovine families could be differentiated. The performances of the RPA assays were validated using 37 milk powder samples, of which 16.2% (6/37) were suspected of being adulterated and 24.3% (9/37) were potentially at risk of being wrongly identified as adulteration. The effectiveness of the developed assays for crude DNA detection was also validated by a rapid nucleic acid extraction kit, and results showed that the presence of large amounts of protein and fat did not affect the qualitative results. Therefore, these assays could combine with the rapid nucleic acids extraction methods for being used in field detection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The polymetallic mineral samples in Pan-Xi region are rich in rare earth resources, and exploring an efficient and accurate analysis method is of great significance for their comprehensive utilization. In this study, the samples were decomposed by three methods, namely closed acid dissolution, open acid dissolution with five acid and alkali fusion with sodium peroxide, and the 15 REE were determined by inductively coupled plasma mass spectrometry (ICP-MS) with Rh and Re as internal standard correction elements. The comparative experiments were conducted using standard substances, and the results showed: (1) The detection limit of closed acid dissolution method was low with relative standard deviation (RSD) ranging from 2.51% to 9.56% and the accuracy of method (ΔlgC) ranging from 0.006 to 0.073, while the sample processing was long, and the results of some REE were low. (2) The RSD of open acid dissolution with five acid method ranged from 1.93% to 7.96%, and ΔlgC ranged from 0.004 to 0.045 with low results of the determination results of REE. (3) The alkali fusion with sodium peroxide method eliminated the influence of matrix effects by selecting instrument optimization, sample dilution, appropriate internal standard elements, etc. The RSD ranged from 1.24% to 6.49%, and ΔlgC ranged from 0.001 to 0.032. In conclusion, alkali fusion with sodium peroxide method has a fast analysis process, complete sample dissolution, and the accuracy and precision of test results can meet the requirements of specification (DZ/T0011-2015), which is most suitable for the analysis of REE in polymetallic mineral samples from Pan-Xi region., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, revealing an autoinhibitory N-terminal peptide that must dissociate to permit subsequent substrate recruitment. Guided by these molecular insights, we design an inhibitory peptide that could block substrate entry into the transport pathway. We also identify a regulatory motif, comprising a positively charged cluster and hydrophobic patches, within the first nucleotide-binding domain that modulates hMRP5 localization by engaging with membranes. By integrating our structural, biochemical, computational, and cell biological findings, we propose a model for hMRP5 conformational cycling and localization. Overall, this work provides mechanistic understanding of hMRP5 function, while informing future selective hMRP5 inhibitor development. More broadly, this study advances our understanding of the structural dynamics and inhibition of ABC transporters., (© 2024. The Author(s).)

Cassava ( Manihot esculenta ) is among the most important staple crops globally, with an imperative role in supporting the Sustainable Development Goal of 'Zero hunger'. In sub-Saharan Africa, it is cultivated mainly by millions of subsistence farmers who depend directly on it for their socio-economic welfare. However, its yield in some regions has been threatened by several diseases, especially the cassava brown streak disease (CBSD). Changes in climatic conditions enhance the risk of the disease spreading to other planting regions. Here, we characterise the current and future distribution of cassava, CBSD and whitefly Bemisia tabaci species complex in Africa, using an ensemble of four species distribution models (SDMs): boosted regression trees, maximum entropy, generalised additive model, and multivariate adaptive regression splines, together with 28 environmental covariates. We collected 1,422 and 1,169 occurrence records for cassava and Bemisia tabaci species complex from the Global Biodiversity Information Facility and 750 CBSD occurrence records from published literature and systematic surveys in East Africa. Our results identified isothermality as having the highest contribution to the current distribution of cassava, while elevation was the top predictor of the current distribution of Bemisia tabaci species complex. Cassava harvested area and precipitation of the driest month contributed the most to explain the current distribution of CBSD outbreaks. The geographic distributions of these target species are also expected to shift under climate projection scenarios for two mid-century periods (2041-2060 and 2061-2080). Our results indicate that major cassava producers, like Cameron, Ivory Coast, Ghana, and Nigeria, are at greater risk of invasion of CBSD. These results highlight the need for firmer agricultural management and climate-change mitigation actions in Africa to combat new outbreaks and to contain the spread of CBSD., Competing Interests: The authors declare there are no competing interests., (©2024 Sikazwe et al.)

Cancer stem cells (CSCs) are a sub-population of cells possessing high tumorigenic potential, which contribute to therapeutic resistance, metastasis and recurrence. Eradication of CSCs is widely recognized as a crucial factor in improving patient prognosis, yet the effective targeting of these cells remains a major challenge. Here, we show that the lysosomal cation channel TRPML1 represents a promising target for CSCs. TRPML1 is highly expressed in breast cancer cells and exhibits sensitivity to salinomycin, a drug known to selectively eliminate CSCs. Pharmacological inhibition and genetic depletion of TRPML1 promote ferroptosis in breast CSCs, reduce their stemness, and enhance the sensitivity of breast cancer cells to chemotherapy drug doxorubicin. The inhibition and knockout of TRPML1 also demonstrate significant suppression of tumor formation and growth in the mouse xenograft model. These findings suggest that targeting TRPML1 to eliminate CSCs may be an effective strategy for the treatment of breast cancer., (© 2024. The Author(s).)

The identification and quantification of the ecological risks, sources and distribution of heavy metals in purple soils are essential for regional pollution control and management. In this study, geo-accumulation index (I geo ), enrichment factor (EF), pollution index (PI), potential ecological risk index (RI), principal component analysis (PCA) model and geographical detector (GD) were combined to evaluate the status, ecological risk, and sources of heavy metals (HMs) in soils from a typical purple soil areas of Sichuan province. The results showed that the average contents of As, Cd, Cr, Cu, Hg, Ni, Pb and Zn in purple soil were 7.77, 0.19, 69.5, 27.9, 0.077, 30.9, 26.5 mg/kg and 76.8 mg/kg, and the I geo , EF and RI of topsoil Hg and Cd in designated area was the highest, and the average contents of Hg and Cd in topsoil were obviously greater than respective soil background value in Sichuan province and purple soil. The hot spots for the spatial distribution of 8 HMs were mainly focused in the southwest and northeast of the designated area, and there were also significant differences for 8 HMs distribution characteristics in the profile soil. Cu comes from both anthropogenic and natural sources, Zn, Ni and Cr mainly come from natural sources, but As, Pb, Hg and Cd mainly derived from human activities. GD results showed that soil texture (X 18 ), altitude (X 4 ), total nitrogen (TN), clay content (X 3 ), sand content (X 2 ) and silt content (X 1 ) had the greatest explanatory power to 8 HMs spatial differentiation.This study provides a reference for understanding the status and influencing factors of HM pollution in typical purple soil, and lays a theoretical foundation for the environmental treatment of purple soil in China., (© 2024. The Author(s).)

The contamination and quantification of soil potentially toxic elements (PTEs) contamination sources and the determination of driving factors are the premise of soil contamination control. In our study, 788 soil samples from the National Agricultural Park in Chengdu, Sichuan Province were used to evaluate the contamination degree of soil PTEs by pollution factors and pollution load index. The source identification of soil PTEs was performed using positive matrix decomposition (PMF), edge analysis (UNMIX) and absolute principal component score-multiple line regression (APCS-MLR). The geo-detector method (GDM) was used to analysis drivers of soil PTEs pollution sources to help interpret pollution sources derived from receptor models. Result shows that soil Cu, Pb, Zn, Cr, Ni, Cd, As and Hg average content were 35.2, 32.3, 108.9, 91.9, 37.1, 0.22, 9.76 and 0.15 mg/kg in this study area. Except for As, all are higher than the corresponding soil background values in Sichuan Province. The best performance of APCS-MLR was determined by comparison, and APCS-MLR was considered as the preferred receptor model for soil PTEs source distribution in the study area. ACPS-MLR results showed that 82.70% of Cu, 61.6% of Pb, 75.3% of Zn, 91.9% of Cr and 89.4% of Ni came from traffic-industrial emission sources, 60.9% of Hg came from domestic-transportation emission sources, 57.7% of Cd came from agricultural sources, and 89.5% of As came from natural sources. The GDM results showed that distance from first grade highway, population, land utilization and total potassium (TK) content were the main driving factors affecting these four sources, with q values of 0.064, 0.048, 0.069 and 0.058, respectively. The results can provide reference for reducing PTEs contamination in farmland soil., (© 2024. The Author(s).)

Alpha-fetoprotein (AFP), a serum glycoprotein, is expressed during embryonic development and the pathogenesis of liver cancer. It serves as a clinical tumor marker, function as a carcinogen, immune suppressor, and transport vehicle; but the detailed AFP structural information has not yet been reported. In this study, we used single-particle cryo-electron microscopy(cryo-EM) to analyze the structure of the recombinant AFP obtained a 3.31 Å cryo-EM structure and built an atomic model of AFP. We observed and identified certain structural features of AFP, including N-glycosylation at Asn251, four natural fatty acids bound to distinct domains, and the coordination of metal ions by residues His22, His264, His268, and Asp280. Furthermore, we compared the structural similarities and differences between AFP and human serum albumin. The elucidation of AFP's structural characteristics not only contributes to a deeper understanding of its functional mechanisms, but also provides a structural basis for developing AFP-based drug vehicles., (© 2024. The Author(s).)

Lysosomes are degradation centers of cells and intracellular hubs of signal transduction, nutrient sensing, and autophagy regulation. Dysfunction of lysosomes contributes to a variety of diseases, such as lysosomal storage diseases (LSDs) and neurodegeneration, but the mechanisms are not well understood. Altering lysosomal activity and examining its impact on the occurrence and development of disease is an important strategy for studying lysosome-related diseases. However, methods to dynamically regulate lysosomal function in living cells or animals are still lacking. Here, we constructed lysosome-localized optogenetic actuators, named lyso-NpHR3.0, lyso-ArchT, and lyso-ChR2, to achieve optogenetic manipulation of lysosomes. These new actuators enable light-dependent control of lysosomal membrane potential, pH, hydrolase activity, degradation, and Ca2+ dynamics in living cells. Notably, lyso-ChR2 activation induces autophagy through the mTOR pathway, promotes Aβ clearance in an autophagy-dependent manner in cellular models, and alleviates Aβ-induced paralysis in the Caenorhabditis elegans model of Alzheimer's disease. Our lysosomal optogenetic actuators supplement the optogenetic toolbox and provide a method to dynamically regulate lysosomal physiology and function in living cells and animals., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zeng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)