Causal Relationship Between Micronutrient and Sleep Disorder: A Mendelian Randomization Study.

Background: Sleep played an important part in human health, and COVID-19 led to a continuous deterioration of sleep. However, the causal relationship between micronutrient and sleep disorder was not yet fully understood. Methods: In this research, the genetic causal relationship between micronutrient and sleep disorder was analyzed utilizing a two-sample Mendelian randomization (MR). Single nucleotide polymorphisms (SNPs) were used as instrumental variables. The analyses were conducted using the MR-Egger, inverse variance weighted, weighted mode, weighted median, simple mode, Cochran's Q test and leave-one-out. Results: Our results suggested that 8 genetically predicted micronutrients participated in sleep disorders, including liver iron (L-iron) and iron in sleeping too much, spleen iron (S-iron) in sleeplessness/insomnia, trouble falling or staying asleep, sleep duration (undersleepers) and nonorganic sleeping disorders, iron metabolism disorder (IMD) and vitamin B12 deficiency anaemia (VB12DA) in narcolepsy, urine sodium (uNa) in narcolepsy, sleep apnea syndrome and sleep disorder, vitamin D (VD) in sleep duration (oversleepers), 25-Hydroxyvitamin D (25(OH)D) in trouble falling or staying asleep. Conclusion: Our study used Mendelian randomization methods at the SNP level to explore the potential causal relationship among L-iron, iron, S-iron, IMD, uNa, 25(OH)D, VD, VB12DA with certain sleep disorder subtypes. Our results uncovered a micronutrient-based strategy for alleviating sleep disorder symptoms.

Regional biomechanical characterization of the spinal cord tissue: dynamic mechanical response.

Characterizing the dynamic mechanical properties of spinal cord tissue is deemed important for developing a comprehensive knowledge of the mechanisms underlying spinal cord injury. However, complex viscoelastic properties are vastly underexplored due to the spinal cord shows heterogeneous properties. To investigate regional differences in the biomechanical properties of spinal cord, we provide a mechanical characterization method (i.e., dynamic mechanical analysis) that facilitates robust measurement of spinal cord ex vivo, at small deformations, in the dynamic regimes. Load-unload cycles were applied to the tissue surface at sinusoidal frequencies of 0.05, 0.10, 0.50 and 1.00 Hz ex vivo within 2 h post mortem. We report the main response features (e.g., nonlinearities, rate dependencies, hysteresis and conditioning) of spinal cord tissue dependent on anatomical origin, and quantify the viscoelastic properties through the measurement of peak force, moduli, and hysteresis and energy loss. For all three anatomical areas (cervical, thoracic, and lumbar spinal cord tissues), the compound, storage, and loss moduli responded similarly to increasing strain rates. Notably, the complex modulus values of ex vivo spinal cord tissue rose nonlinearly with rising test frequency. Additionally, at every strain rate, it was shown that the tissue in the thoracic spinal cord was significantly more rigid than the tissue in the cervical or lumbar spinal cord, with compound modulus values roughly 1.5-times that of the lumbar region. At strain rates between 0.05 and 0.50 Hz, tan δ values for thoracic (that is, 0.26, 0.25, 0.06, respectively) and lumbar (that is, 0.27, 0.25, 0.07, respectively) spinal cord regions were similar, respectively, which were higher than cervical (that is, 0.21, 0.21, 0.04, respectively) region. The conditioning effects tend to be greater at relative higher deformation rates. Interestingly, no marked difference of conditioning ratios is observed among all three anatomical regions, regardless of loading rate. These findings lay a foundation for further comparison between healthy and diseased spinal cord to the future development of spinal cord scaffold and helps to advance our knowledge of neuroscience.

A ferrous fluorescence lifetime response probe for monitoring changes in lipid droplets during ferroptosis and imaging in liver disease model.

Ferrous ions (Fe2⁺) accumulation and abnormal alterations in lipid droplets (LDs) are closely associated with ferroptosis. In the liver, excessive iron accumulation promotes oxidative stress and exacerbates lipid droplet accumulation, while the disruption of iron homeostasis may also affect the formation and size of lipid droplets, their increased number and size can exacerbate the severity of disease under fatty liver conditions. The leads to hepatocyte damage, further triggering liver inflammation, fibrosis, and ultimately resulting in cirrhosis and hepatocellular carcinoma. Therefore, real-time monitoring of iron ion and lipid droplet changes is crucial for assessing the severity of liver disease, disease progression, and understanding the mechanisms of ferroptosis. We have developed a fluorescent probe, NRFep, for real-time monitoring of iron ion fluctuations and visualization of lipid droplet changes in ferroptosis and liver disease models. NRFep is specific and sensitive to iron ions and exhibits excellent stability in both cells and animal models. In addition, NRFep can be used to monitor changes in iron ions and lipid droplets in mouse liver injury and fatty liver models. Through fluorescence lifetime imaging technology, NRFep can also study the dynamic changes of intracellular iron ion content. NRFep provides a powerful tool for studying ferroptosis and related diseases, and its unique dual-monitoring function opens up new possibilities for developing new diagnostic and therapeutic strategies.

MIF aggravates experimental autoimmune prostatitis through activation of the NLRP3 inflammasome via the PI3K/AKT pathway.

In our investigation, we investigated the role of macrophage migration inhibitory factor (MIF), a key cytokine, in chronic nonbacterial prostatitis (CNP), an underexplored pathology. Elevated MIF expression was observed in the serum of individuals with chronic prostatitis-like symptoms (CP-LS) as well as in serum and tissue samples from experimental autoimmune prostatitis (EAP) mouse model. Treatment with ISO-1, a specific MIF antagonist, effectively mitigated prostatic inflammation and macrophage infiltration, thereby emphasizing the critical role of MIF in orchestrating immune responses within the prostate microenvironment. Further analyses revealed that MIF stimulates the PI3K/AKT and NLRP3 inflammasome pathways, which are integral to inflammation and cellular immunity. Pharmacological inhibition of the PI3K/AKT pathway by LY294002 substantially reduced prostatic inflammation and macrophage infiltration, potentially by inhibiting NLRP3 inflammasome activation. These findings collectively suggest that MIF is a potential diagnostic marker for CNP and suggest that targeting MIF or its downstream signalling pathways, PI3K/AKT and NLRP3, might represent a novel therapeutic strategy for this condition.

Rational design of a two-dimensional high-temperature ferromagnet from HCP cobalt.

Cobalt has the highest Curie temperature (Tc) among the elemental ferromagnetic metals and has a hexagonal close-packed (HCP) structure at room temperature. In this study, HCP Co was thinned to the thickness of several (n) unit cells along the c-axis and then passivated by halogen atoms, thus being named Co2nX2 (X = F, Cl, Br and I). For Co2X2 and Co3X2, all of them are not only kinetically but also thermodynamically stable from the viewpoint of the phonon spectra and molecular dynamics. Similar to HCP Co, two-dimensional (2D) Co2F2, Co2Cl2 and Co3X2 (X = Cl, Br and I) are still ferromagnetic metals within the Stoner model but Co2X2 (X = Br and I) is a ferromagnetic half-metal with the coexistence of the metallic behavior for one spin and the insulating behavior for the other spin. Taking into account the spin-orbital coupling (SOC), the easy-magnetization axis is within the plane where the magnetization is isotropic, making it look like a 2D XY magnet. Applying a critical biaxial strain could lead to an easy-magnetization axis changing from the in-plane to the out-of-plane direction. Finally, we use classical Monte Carlo simulations to estimate the Curie temperature (Tc) which is as high as 957 and 510 K for Co2F2 and Co2Cl2, respectively, because of the strong direct exchange interaction. Different from being obtained by mechanical or liquid exfoliation from van der Waals layered structures, our study opens up new possibilities to search for novel 2D ferromagnets from the elemental ferromagnets and provides opportunities for realizing realistic ultra-thin spintronic devices.

The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity.

The human genome contains 24 gag-like capsid genes derived from deactivated retrotransposons conserved among eutherians. Although some of their encoded proteins retain the ability to form capsids and even transfer cargo, their fitness benefit has remained elusive. Here we show that the gag-like genes PNMA1 and PNMA4 support reproductive capacity during aging. Analysis of donated human ovaries shows that expression of both genes declines normally with age, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. Six-week-old mice lacking either Pnma1 or Pnma4 are indistinguishable from wild-type littermates, but by six months the mutant mice become prematurely subfertile, with precipitous drops in sex hormone levels, gonadal atrophy, and abdominal obesity; overall they produce markedly fewer offspring than controls. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes.

Comparison of feasibility and effectiveness of tunneled dialysis catheter placement with or without DSA guidance: a propensity score-matched cohort study.

BACKGROUND: In some resource-limited regions, the placement of tunneled dialysis catheters (TDC) is often preferred under ultrasound guidance rather than fluoroscopy. This study compared ultrasound-and digital subtraction angiography-guided (DSA)-guided TDC in renal replacement therapy. METHODS: This retrospective cohort study included all TDC placements performed at our hospital between January 2020 and October 2022. We utilized 1:1 propensity score matching (PSM) to balance the demographic and clinical characteristics of the DSA-guided and ultrasound-guided groups. Dialysis prescriptions and actual dialysis completion were assessed using intraclass correlation coefficients (ICC). Multivariable logistic regression analyses determined the risk factors for early termination of dialysis. The differences in adverse events, catheter function, and catheter tip position were evaluated between the two groups. RESULTS: The study included 261 patients (142 in the DSA-guided group and 119 in the ultrasound-guided group). After PSM, 91 patients were included in each group, with no significant baseline differences (p > .1). Both groups achieved adequate catheter blood flow and ultrafiltration volumes without deviations from dialysis prescriptions (ICC ≥ 0.75). The DSA-guided group had fewer early dialysis terminations than the ultrasound-guided group (3.3 vs. 12.0%, p = .026). The position of the catheter tip in the right atrium was more consistent in the DSA-guided group (100 vs. 74.2%, p < .001). CONCLUSION: Hemodialysis catheters inserted under DSA guidance exhibited superior performance compared to those inserted under ultrasound guidance, primarily due to more accurate catheter tip positioning. DSA guidance is recommended when ensuring optimal catheter tip placement.

[Mechanism of Huangqin Qingre Chubi Capsules regulating p53/p21 signaling pathway to delay chondrocyte senescence in osteoarthritic rats].

This study aims to investigate the mechanism of Huangqin Qingre Chubi Capsules(HQC) in delaying chondrocyte senescence of osteoarthritic(OA) rats by regulating the p53/p21 signaling pathway. Rheumatic fever paralysis models of OA rats were induced based on monosodiun iodoacetate(MIA) combined with external rheumatic fever environmental stimuli and divided into normal(Con) group, OA model(MIA) group, OA model+rheumatic fever stimulation model(MIA-M) group, MIA-M+HQC low-dose(MIA-M+HQC-L) group, medium-dose(MIA-M+HQC-M) group, and high-dose(MIA-M+HQC-H) group, and MIA-M+glucosamine(MIA-M+GS) group. The models were successfully prepared and administered by gavage for 30 d. The pathological changes of cartilage were observed by hematoxylin-eosin(HE) and Senna O solid green(SO) staining. The expression of interleukin(IL)-1ß and IL-6 was detected by enzyme-linked immunosorbent assay(ELISA). Flow cytometry(FCM) was used to detect apoptosis and cell cycle. The mRNA expression of MMP13, ADAMTS-5, COLⅡ, and TGF-ß was detected by RT-qPCR. The protein expression of p53/p21, p16, Bax, and Bcl-2 was detected by Western blot. The articular cartilage surface of rats in the Con group was smooth, and the tide line was smooth. The cartilage layer of MIA and MIA-M groups was obviously damaged, and the cartilage matrix was reduced. The above conditions were more severe in the MIA-M group. The cartilage surface of the HQC high-dose group and MIA-M+GS group was basically intact with clear delamination. Compared with the MIA-M+HQC-H group, Mankin's score was higher in the HQC low-dose and medium-dose groups, and the change was not obvious in the MIA-M+GS group. Compared with the Con group, the proportion of chondrocytes G_1 was elevated in the MIA and MIA-M groups, and the proportion of the S phase and G_2 phase was significantly decreased. In addition, the apoptosis rate was increased. Compared with MIA-M, HQC groups inhibited apoptosis and promoted cell proliferation in a concentration-dependent manner. Compared with the MIA-M+HQC-H group, the effect was more significant in the HQC high-dose group than in the HQC medium-low dose, while it was not significant in the MIA-M+GS group. Compared with the Con group, IL-1ß and IL-6 were elevated in the MIA and MIA-M groups, and mRNA levels of MMP13 and ADAMTS-5 were elevated. p53, p21, p16, and Bax protein were elevated, and mRNA levels of COLⅡ and TGF-ß were decreased. Compared with the MIA-M group, IL-1ß and IL-6 decreased after drug interventions of HQC and GS, and mRNA levels of MMP13 and ADAMTS-5, as well as protein levels of p53, p21, Bax, and p16 decreased. In addition, Bcl-2 increased. The improvement of these indexes was significantly better in the MIA-M+HQC-H group than in the HQC low-dose and medium-dose groups, and the difference with the MIA-M+GS group was not significant. HQC delayed MIA-induced chondrocyte senescence in OA rats, inhibited inflammatory response and extracellular matrix(ECM) degradation, and its mechanism may be related to the inhibition of the p53/p21 pathway.

Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer.

Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.

The interplay between cytokines and stroke: a bi-directional Mendelian randomization study.

Stroke, the second leading cause of death and disability, causes massive cell death in the brain followed by secondary inflammatory injury initiated by disease associated molecular patterns released from dead cells. Nonetheless, the evidence regarding the causal relationship between inflammatory cytokines and stroke subtypes is obscure. To leverage large scale genetic association data to investigate the interplay between circulating cytokines and stroke, we adopted a two-sample bi-directional Mendelian randomization (MR) analysis. Firstly, we performed a forward MR analysis to examine the associations of genetically determined 31 cytokines with 6 stroke subtypes. Secondly, we conducted a reverse MR analysis to check the associations of 6 stroke subtypes with 31 cytokines. In the forward MR analysis, genetic evidence suggests that 21 cytokines were significantly associated with certain stroke subtype risk with |ß| ranging from 1.90 × 10-4 to 0.74. In the reverse MR analysis, our results found that five stroke subtypes (intracerebral hemorrhage (ICH), large artery atherosclerosis ischemic stroke (LAAS), lacunar stroke (LS), cardioembolic ischemic stroke (CEI), small-vessel ischemic stroke (SV)) caused significantly changes in 16 cytokines with |ß| ranging from 1.08 × 10-4 to 0.69. In particular, those five stroke subtypes were statistically significantly associated with C-reactive protein (CRP). In addition, ICH, LAAS, LS and SV were significantly correlated with vascular endothelial growth factor (VEGF), while LAAS, LS, CEI and SV were significantly related to fibroblast growth factor (FGF). Moreover, integrated bi-directional MR analysis, these factors (IL-3Rα, IL-6R, IL-6Rα, IL-1Ra, insulin-like growth factor-1(IGF-1), IL-12Rß2) can be used as predictors of some specific stroke subtypes. As well as, IL-16 and C-C motif chemokine receptor 7 (CCR7) can be used as prognostic factors of stroke. Our findings prognostic identify potential pharmacological opportunities, including perturbation of circulating cytokines for both predicting stroke risk and post stroke treatment effects. As we conducted a comprehensive search and analysis of stroke subtype and cytokines in the existing publicly available GWAS database, the results have good population-generalizability.

A novel method combining deep learning with the Kennard-Stone algorithm for training dataset selection for image-based rice seed variety identification.

BACKGROUND: Different varieties of rice vary in planting time, stress resistance, and other characteristics. With advances in rice-breeding technology, the number of rice varieties has increased significantly, making variety identification crucial for both trading and planting. RESULTS: This study collected RGB images of 20 hybrid rice seed varieties. An enhanced deep super-resolution network (EDSR) was employed to enhance image resolution, and a variety classification model utilizing the high-resolution dataset demonstrated superior performance to that of the model using the low-resolution dataset. A novel training sample selection methodology was introduced integrating deep learning with the Kennard-Stone (KS) algorithm. Convolutional neural networks (CNN) and autoencoders served as supervised and unsupervised feature extractors, respectively. The extracted feature vectors were subsequently processed by the KS algorithm to select training samples. The proposed methodologies exhibited superior performance over the random selection approach in rice variety classification, with an approximately 10.08% improvement in overall classification accuracy. Furthermore, the impact of noise on the proposed methodology was investigated by introducing noise to the images, and the proposed methodologies maintained superior performance relative to the random selection approach on the noisy image dataset. CONCLUSION: The experimental results indicate that both supervised and unsupervised learning models performed effectively as feature extractors, and the deep learning framework significantly influenced the selection of training set samples. This study presents a novel approach for training sample selection in classification tasks and suggests the potential for extending the proposed method to image datasets and other types of datasets. Further exploration of this potential is warranted. © 2024 Society of Chemical Industry.

Simultaneous determination of pigments of spinach (Spinacia oleracea L.) leaf for quality inspection using hyperspectral imaging and multi-task deep learning regression approaches.

Rapid and accurate determination of pigment content is important for quality inspection of spinach leaves during storage. This study aimed to use hyperspectral imaging at two spectral ranges (visible/near-infrared, VNIR: 400-1000 nm; NIR: 900-1700 nm) to simultaneously determine the pigment (chlorophyll a, chlorophyll b, total chlorophyll, and carotenoids) content in spinach stored at different durations and conditions (unpackaged and packaged). Partial least squares (PLS), back propagation neural network (BPNN) and convolutional neural network (CNN) were used to establish single-task and multi-task regression models. Single-task CNN (STCNN) models and multi-task CNN (MTCNN) models obtained better performances than the other models. The models using VNIR spectra were superior to those using NIR spectra. The overall results indicated that hyperspectral imaging with multi-task learning could predict the quality attributes of spinach simultaneously for spinach quality inspection under various storage conditions. This research will guide food quality inspection by simultaneously inspecting multiple quality attributes.

γ-Glutamyltranspeptidase fluorescence lifetime response probe for precision tumor detection unveiling A549 cancer cell specificity.

γ-Glutamyltranspeptidase (γ-GGT), as a key enzyme, exhibits markedly higher expression levels in tumor cells compared to normal cells. Under normal conditions, γ-GGT activity on the cell membrane is relatively low, but it undergoes a significant upregulation in cancer cells, making it a potential cancer biomarker. Particularly in A549 cells, a prominent cancer cell line, the pronounced upregulation of γ-GGT expression emphasizes its potential as a unique recognition target and a robust marker for A549 cells. This study successfully synthesized a highly selective γ-GGT fluorescent probe, the exhibits commendable sensitivity (LOD = 0.0021U/mL) and selectivity, achieving efficient detection at the cellular level and providing accurate insights into differential expression between normal and cancer cells. The alterations in fluorescence lifetime observed before and after the probe's reaction with γ-GGT serve as a crucial foundation for fluorescence lifetime imaging on living cells. The probe has become a powerful tool for precise localization of tumor cells, particularly demonstrating its capability for specific recognition in A549 cells. Overall, this research highlights the potential of γ-GGT as a target for fluorescent probes, emphasizing its prospects in specific recognition, particularly in A549 cells, with profound implications for advancing early cancer diagnosis and treatment methods.

Isaridin E Protects against Sepsis by Inhibiting Von Willebrand Factor-Induced Endothelial Hyperpermeability and Platelet-Endothelium Interaction.

Endothelial hyperpermeability is pivotal in sepsis-associated multi-organ dysfunction. Increased von Willebrand factor (vWF) plasma levels, stemming from activated platelets and endothelium injury during sepsis, can bind to integrin αvß3, exacerbating endothelial permeability. Hence, targeting this pathway presents a potential therapeutic avenue for sepsis. Recently, we identified isaridin E (ISE), a marine-derived fungal cyclohexadepsipeptide, as a promising antiplatelet and antithrombotic agent with a low bleeding risk. ISE's influence on septic mortality and sepsis-induced lung injury in a mouse model of sepsis, induced by caecal ligation and puncture, is investigated in this study. ISE dose-dependently improved survival rates, mitigating lung injury, thrombocytopenia, pulmonary endothelial permeability, and vascular inflammation in the mouse model. ISE markedly curtailed vWF release from activated platelets in septic mice by suppressing vesicle-associated membrane protein 8 and soluble N-ethylmaleide-sensitive factor attachment protein 23 overexpression. Moreover, ISE inhibited healthy human platelet adhesion to cultured lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), thereby significantly decreasing vWF secretion and endothelial hyperpermeability. Using cilengitide, a selective integrin αvß3 inhibitor, it was found that ISE can improve endothelial hyperpermeability by inhibiting vWF binding to αvß3. Activation of the integrin αvß3-FAK/Src pathway likely underlies vWF-induced endothelial dysfunction in sepsis. In conclusion, ISE protects against sepsis by inhibiting endothelial hyperpermeability and platelet-endothelium interactions.

Influence of Residue Soil on the Properties of Fly Ash-Slag-Based Geopolymer Materials for 3D Printing.

This study investigates the impact of residue soil (RS) powder on the 3D printability of geopolymer composites based on fly ash and ground granulated blast furnace slag. RS is incorporated into the geopolymer mixture, with its inclusion ranging from 0% to 110% of the combined mass of fly ash and finely ground blast furnace slag. Seven groups of geopolymers were designed and tested for their flowability, setting time, rheology, open time, extrudability, shape retention, buildability, and mechanical properties. The results showed that with the increase in RS content, the fluidity of geopolymer mortar decreases, and the setting time increases first and then decreases. The static yield stress, dynamic yield stress, and apparent viscosity of geopolymer mortar increase with the increase in RS content. For an RS content between 10% and 90%, the corresponding fluidity is above 145 mm, and the yield stress is controlled within the range of 2800 Pa, which meets the requirements of extrusion molding. Except for RS-110, geopolymer mortars with other RS contents showed good extrudability and shape retention. The compressive strength of 3D printing samples of geopolymer mortar containing RS has obvious anisotropy.

The retrotransposon - derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity.

The human genome contains 24 gag -like capsid genes derived from deactivated retrotransposons conserved among eutherians. Although some of their encoded proteins retain the ability to form capsids and even transfer cargo, their fitness benefit has remained elusive. Here we show that the gag -like genes PNMA1 and PNMA4 support reproductive capacity. Six-week-old mice lacking either Pnma1 or Pnma4 are indistinguishable from wild-type littermates, but by six months the mutant mice become prematurely subfertile, with precipitous drops in sex hormone levels, gonadal atrophy, and abdominal obesity; overall they produce markedly fewer offspring than controls. Analysis of donated human ovaries shows that expression of both genes declines normally with aging, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes.

Two-component system RstAB promotes the pathogenicity of adherent-invasive Escherichia coli in response to acidic conditions within macrophages.

Adherent-invasive Escherichia coli (AIEC) strain LF82, isolated from patients with Crohn's disease, invades gut epithelial cells, and replicates in macrophages contributing to chronic inflammation. In this study, we found that RstAB contributing to the colonization of LF82 in a mouse model of chronic colitis by promoting bacterial replication in macrophages. By comparing the transcriptomes of rstAB mutant- and wild-type when infected macrophages, 83 significant differentially expressed genes in LF82 were identified. And we identified two possible RstA target genes (csgD and asr) among the differentially expressed genes. The electrophoretic mobility shift assay and quantitative real-time PCR confirmed that RstA binds to the promoters of csgD and asr and activates their expression. csgD deletion attenuated LF82 intracellular biofilm formation, and asr deletion reduced acid tolerance compared with the wild-type. Acidic pH was shown by quantitative real-time PCR to be the signal sensed by RstAB to activate the expression of csgD and asr. We uncovered a signal transduction pathway whereby LF82, in response to the acidic environment within macrophages, activates transcription of the csgD to promote biofilm formation, and activates transcription of the asr to promote acid tolerance, promoting its replication within macrophages and colonization of the intestine. This finding deepens our understanding of the LF82 replication regulation mechanism in macrophages and offers new perspectives for further studies on AIEC virulence mechanisms.

Harnessing developmental dynamics of spinal cord extracellular matrix improves regenerative potential of spinal cord organoids.

Neonatal spinal cord tissues exhibit remarkable regenerative capabilities as compared to adult spinal cord tissues after injury, but the role of extracellular matrix (ECM) in this process has remained elusive. Here, we found that early developmental spinal cord had higher levels of ECM proteins associated with neural development and axon growth, but fewer inhibitory proteoglycans, compared to those of adult spinal cord. Decellularized spinal cord ECM from neonatal (DNSCM) and adult (DASCM) rabbits preserved these differences. DNSCM promoted proliferation, migration, and neuronal differentiation of neural progenitor cells (NPCs) and facilitated axonal outgrowth and regeneration of spinal cord organoids more effectively than DASCM. Pleiotrophin (PTN) and Tenascin (TNC) in DNSCM were identified as contributors to these abilities. Furthermore, DNSCM demonstrated superior performance as a delivery vehicle for NPCs and organoids in spinal cord injury (SCI) models. This suggests that ECM cues from early development stages might significantly contribute to the prominent regeneration ability in spinal cord.

Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity.

Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.

A novel near-infrared fluorescent probe for real-time monitoring of leucine aminopeptidase activity and metastatic tumor progression.

This article discusses the importance of early tumor detection, particularly in liver cancer, and the role of leucine aminopeptidase (LAP) as a potential marker for liver cancer diagnosis and prognosis assessment. The article highlights the limitations of current tumor markers and the need for new markers and multi-marker approaches to improve accuracy. The authors introduce a novel near-infrared fluorescent probe, NTAP, designed for LAP detection. They describe the synthesis of the probe and evaluate its spectral properties, including the LOD was 0.0038 U/mL, and QY was 0.32 %. The kinetic properties of NTAP, such as the relationship between LAP concentration (0-0.08 U/mL), reaction time (3 min), and fluorescence excitation spectra (475 nm) and emission spectra (715 nm) are investigated. The article also discusses the stability and selectivity of the probe and its ability to detect LAP in complex samples. Cellular imaging experiments demonstrate the NATP specificity and selectivity in detecting LAP activity and its inhibition. Animal models of liver and lung metastasis are used to evaluate the probe's imaging capabilities, showing its ability to accurately locate and detect metastatic lesions. The article concludes by emphasizing the potential applications of the NTAP probe in early tumor diagnosis, treatment monitoring, and the study of tumor metastasis mechanisms.