Signal Response Research Articles

Impact of zinc supplementation on cellular and molecular biomechanical alterations and critical outcomes in pediatric patients with sepsis: A randomized controlled trial

Background: Sepsis remains a significant contributor to illness and death in children. Studies suggests that potential benefits of zinc supplementation in patients with sepsis, such as reduced inflammation and mortality rates. Zinc is involved in maintaining the structural integrity and function of cell membranes, which is essential for proper cell signaling and biomechanical responses. It can also influence the activity of key enzymes and proteins that regulate intracellular and extracellular forces, thereby affecting cell adhesion, migration, and overall tissue mechanics. Therefore, this study aimed to evaluate the occurrence of Acute Respiratory Distress Syndrome (ARDS), Septic Shock, Acute Kidney Injury (AKI), and Mortality in Pediatric Sepsis receiving Zinc supplementation, with a focus on the underlying cellular and molecular biomechanical mechanisms. Methods: This study was a Randomized Control Trial (RCT) conducted using a parallel-group, double-blind design and prospective cohort approach. Participants were selected through consecutive sampling and then randomized into two groups: one receiving standard therapy plus zinc supplementation and the other receiving standard therapy plus a placebo. Results: Among pediatric patients with sepsis, the incidence of septic shock was significantly lower in the group receiving standard therapy with zinc supplementation (34.4%) compared to the placebo group (65.6%) (p = 0.00, OR 2.29, 95% CI: 1.28–4.11). The incidence of ARDS was 66.7% in the placebo group, versus 33.3% in the zinc group (p = 0.00, OR 0.37, 95% CI: 0.22–0.64). For acute kidney injury (AKI), 65.7% occurred in the placebo group compared to 34.3% in the zinc group (p = 0.04, OR 2.09, 95% CI: 0.99–4.40). Mortality in the placebo group was 64.3%, while in the zinc group it was 35.7% (p = 0.01, OR 0.48, 95% CI: 0.26–0.88). Conclusion: Zinc supplementation significantly reduces the incidence of acute respiratory distress syndrome, acute kidney injury, septic shock, and mortality in pediatric patients with sepsis. These outcomes may be attributed to zinc’s role in modulating cellular signaling pathways, enhancing cellular integrity under stress, and improving the biomechanical properties of cell membranes, thereby promoting better physiological responses in the context of sepsis.

A conserved element in the first intron of Cd4 has a lineage specific, TCR signal-responsive, canonical enhancer function that matches the timing of cell surface CD4 upregulation required to prevent lineage choice error

IntroductionThe regulation of Cd4 expression during T-cell development and immune responses is essential for proper lineage commitment and function in the periphery. However, the mechanisms of genetic and epigenetic regulation are complex, and their interplay not entirely understood. Previously, we demonstrated the need for CD4 upregulation during positive selection to ensure faithful commitment of MHC-II-restricted T cells to the CD4 lineage. In this study, we investigate whether a conserved region, here called NCE, that is proximal to the Cd4 silencer and contains E4m has the required developmental-stage-specific canonical enhancer function and TCR responsiveness to mediate the CD4 upregulation required to prevent lineage errors.MethodsTo investigate the role of NCE, transient transfection of reporter plasmids was performed in thymoma cell lines arrested at the double-positive (DP, CD4+CD8+) and intermediate (INT, CD4+CD8lo) stages of development. CRISPR/Cas9-mediated deletion of the coreNCE/E4m region was carried out in these cell lines to assess its impact on CD4 surface expression, re-expression rates, and TCR signaling responsiveness. To avoid developmental alterations from direct manipulation of the endogenous Cd4 locus in vivo, BAC-transgenic reporter mice were generated with the locus modified to express EGFP in the presence or absence of NCE. EGFP mRNA levels were measured via RT-qPCR, and EGFP fluorescence was analyzed in post-selection thymocytes.ResultsOur in vitro experiments demonstrate that NCE by itself can function as an enhancer at the INT, but not the DP stage of development. Furthermore, CRISPR/Cas9-mediated deletion of coreNCE/E4m resulted in reduced CD4 surface levels, slower re-expression rates, and reduced TCR signaling responsiveness in INT cells, but not in DP cells. In vivo, NCE-sufficient transgenic mice exhibited upregulation of Cd4 reporter EGFP mRNA levels at the INT stage and a corresponding upregulation of EGFP fluorescence, whereas NCE-deficient mice showed a significant loss of Cd4 reporter EGFP mRNA and no detectable EGFP production in any post-selection thymocytes.DiscussionThis study demonstrates that the canonical enhancer function of coreNCE/E4m is essential for CD4 upregulation following positive selection. The NCE region, with its developmental-stage-specific activity and its known epigenetic regulatory capabilities, ensures faithful lineage commitment to the CD4 lineage.

Tb-based Metal-Organic Framework-Referenced Fluorescence Assay for Distinguishing Hydroquinone from Its Isomers and Subsequent Quantitative Visual Detection of Cu2.

Hydroquinone (HQ) and copper ions (Cu2+) are categorized as environmental pollutants that are severely limited in water. Designing a selective assay for discriminating HQ from its two isomers and the convenient determination of Cu2+ is of great importance. Herein, a Tb-based metal-organic framework (Tb-MOF) and HQ are assembled innovatively into a ratiometric fluorescence nanoprobe to selectively distinguish HQ and subsequent quantitative visual detection of Cu2+. The native blue emission of HQ at 338 nm is used as a response signal, while Tb-MOF with green fluorescence offers a reference signal at 545 nm. Notably, neither resorcinol (RC) nor catechol (CC) exhibits obvious emission under the same experimental conditions, which enables discriminating HQ from its isomers. Thus, a ratiometric fluorescence method has been designed for the selective detection of HQ with the fluorescence intensity ratio F338/F545 as the readout. The redox reaction between HQ and Cu2+ induces fluorescence quenching of HQ and no change to that of Tb-MOF, resulting in a noticeable color variation from blue-green to green via the naked eye. Furthermore, sensitive visual detection of Cu2+ is achieved with a low detection limit of 1.67 μM using a smartphone. The satisfactory recoveries and good repeatability of quantitative visualization determined in spiked water samples make this sensing platform suitable for on-site monitoring of environmental samples.

Decoding imagined movement in people with multiple sclerosis for brain-computer interface translation.

Multiple Sclerosis (MS) is a heterogeneous autoimmune-mediated disorder affecting the central nervous system, commonly manifesting as fatigue and progressive limb impairment. This can significantly impact quality of life due to weakness or paralysis in the upper and lower limbs. A Brain-Computer Interface (BCI) aims to restore quality of life through control of an external device, such as a wheelchair. However, the limited BCI research in people with MS has been confined to exploring the P300 response and brain signals associated with attempted movement. The current study aims to expand the MS-BCI literature by highlighting the feasibility of decoding MS imagined movement.
Approach. We collected electroencephalography (EEG) data from eight participants with various symptoms of MS and ten neurotypical control participants. Participants made imagined movements of the hands and feet as directed by a go no-go protocol. Binary regularised linear discriminant analysis was used to classify imagined movement vs. rest and vs. movement at individual time-frequency points. The frequency bands which provided the maximal accuracy, and the associated latency, were compared.
Main Results. In all MS participants, the classification algorithm achieved above 70% accuracy in at least one imagined movement vs. rest classification and most movement vs. movement classifications. There was no significant difference between classification of limbs with weakness or paralysis to neurotypical controls. Both the MS and control groups possessed decodable information within the alpha (7-13 Hz) and beta (16-30 Hz) bands at similar latency.
Significance. This study is the first to demonstrate the feasibility of decoding imagined movements in people with MS. As an alternative to the P300 response, motor imagery-based control of a BCI may also be combined with existing motor imagery therapy to supplement MS rehabilitation. These promising results merit further long term BCI studies to investigate the effect of MS progression on classification performance.&#xD.

Methylsulfonylmethane (MSM) Supplementation in Adult Horses Supports Improved Skeletal Muscle Inflammatory Gene Expression Following Exercise

Methylsulfonylmethane (MSM) is a sulfur-containing molecule with reported anti-inflammatory and antioxidant activities. Exercise causes the formation of free radicals and stimulates inflammatory gene expression in leukocytes and skeletal muscle. The hypothesis that dietary supplementation with MSM alters the exercise-mediated inflammatory and oxidant response was assessed in unfit adult thoroughbred geldings. Ten geldings (6.7 ± 1.6 yr) were assigned to a diet supplemented without (CON, n = 5) or with 21 g of MSM (n = 5) for 30 days. Following the supplementation period, horses performed a standardized exercise test (SET) with blood collections before (t = 0), 10 min, 1 h, 4 h, and 24 h post-SET. Skeletal muscle biopsies were retrieved from the middle gluteus before and 1 h post-SET for total RNA isolation. All horses were rested for 120 days before the experiment was repeated in a cross-over design. Plasma total antioxidant capacity was unaffected (p > 0.05) by either exercise or MSM. Plasma glutathione peroxidase activity was less (p < 0.05) in MSM horses than in the CON. Plasma IL6, IL8, IL10, and TNFɑ were unaffected (p > 0.05) by either exercise or diet. Transcriptomic analysis of skeletal muscle revealed 35 genes were differentially expressed (DEG; p < 0.05) by 2-fold or more in response to exercise; no MSM DEGs were noted. A comparison of the exercise by diet contrasts revealed that horses supplemented with MSM contained a greater number of exercise-responsive genes (630; logFC > 0.2; q < 0.05) by comparison to the CON (237), with many of these mapping to the immune response (71) and cytokine signal transduction (60) pathways. These results suggest supplementation of MSM as a dietary aid for improved anti-inflammatory responses in skeletal muscle following exercise.

Insights of cellular and molecular changes in sugarcane response to oxidative signaling

Main conclusionSignificant changes in the proteome highlight essential metabolic adaptations for development and oxidative signaling induced by the treatment of young sugarcane plants with hydrogen peroxide. These adaptations suggest that hydrogen peroxide acts not only as a stressor but primarily as a signaling molecule, triggering specific metabolic pathways that regulate growth and plant resilience.Sugarcane is a crucial crop for sugar and ethanol production, often influenced by environmental signals. Hydrogen peroxide (H2O2) is increasingly recognized as an important signaling molecule that regulates plant development and adaptation. In this study, two-month-old sugarcane plants were treated with varying concentrations of H2O2 to investigate how this molecule acts as a signal at the cellular, biochemical, and proteomic levels. Antioxidant enzyme activity exhibited fluctuations, suggesting a dynamic response to oxidative signaling. Lipid peroxidation, observed through TBARs and scanning electron microscopy, highlighted early membrane modifications. Proteomic analysis (ProteomeXchange PXD048142) identified 2,699 proteins, with 155 showing significant expression changes in response to H2O2 signaling. Bioinformatics, including Principal Component Analysis, revealed distinct proteomic profiles in roots and leaves, indicating tissue-specific metabolic reprogramming. Functional annotation through Gene Ontology and KEGG pathway enrichment showed that oxidative signaling led to the repression of photosynthesis-related pathways in leaves, while promoting pathways related to protein processing, glycolysis, and carbon metabolism in roots. Additionally, bioinformatic tools identified proteins involved in amino acid metabolism, the TCA cycle, and carbohydrate metabolism as critical components of sugarcane's adaptive signaling response. The data suggest that sugarcane plants responded to oxidative signals by adjusting their metabolic networks, promoting sustained development and potential pathways for targeted plant breeding.

Involvement of p38 MAPK and MAPKAPK2 in promoting cell death and the inflammatory response to ischemic stress associated with necrotic glioblastoma

The association of necrosis in tumors with poor prognosis implies a potential tumor-promoting role. However, the mechanisms underlying cell death in this context and how damaged tissue contributes to tumor progression remain unclear. Here, we identified p38 mitogen-activated protein kinases (p38 MAPK, a.k.a. p38) as a key player in promoting cell death and the inflammatory response to ischemic stress associated with necrotic tumors. We found that glioblastoma (GBM) cells expressing patient-derived Kirsten rat sarcoma (KRAS) or phosphoinositide-3-kinase (PI3K) active mutants showed enhanced cell death under ischemia-mimetic conditions in vitro and were more likely to develop into necrotic tumors in vivo. Cell death in both settings depended on p38, which is also required for tumor progression driven by KRAS or PI3K. Under ischemia-mimetic conditions, GBM cells undergo reactive oxygen species (ROS)-dependent cell death. Gene expression in these cells recapitulated multiple features observed in peri-necrotic tumors from patient GBM. Further studies showed the involvement of a positive feedback loop between the p38-MAPK-activated protein kinase 2 (MAPKAPK2, a.k.a. MK2) signaling axis and the unfolded protein response signaling components activating transcription factor 4 (ATF4) and inositol-requiring enzyme 1 (IRE1α) in driving ischemic tumor cell death. This signaling cascade was further potentiated by RAS or PI3K activation under ischemic conditions, contributing to the inflammatory gene expression response. Therefore, our study suggests that p38 could be targeted to relieve the inflammatory response in necrotic tumors and inhibit GBM progression.

The dependence of shugoshin on Bub1-kinase activity is dispensable for the maintenance of spindle assembly checkpoint response in Cryptococcus neoformans.

During chromosome segregation, the spindle assembly checkpoint (SAC) detects errors in kinetochore-microtubule attachments. Timely activation and maintenance of the SAC until defects are corrected is essential for genome stability. Here, we show that shugoshin (Sgo1), a conserved tension-sensing protein, ensures the maintenance of SAC signals in response to unattached kinetochores during mitosis in a basidiomycete budding yeast Cryptococcus neoformans. Sgo1 maintains optimum levels of Aurora B kinase Ipl1 and protein phosphatase 1 (PP1) at kinetochores. The absence of Sgo1 results in the loss of Aurora BIpl1 with a concomitant increase in PP1 levels at kinetochores. This leads to a premature reduction in the kinetochore-bound Bub1 levels and early termination of the SAC signals. Intriguingly, the kinase function of Bub1 is dispensable for shugoshin's subcellular localization. Sgo1 is predominantly localized to spindle pole bodies (SPBs) and along the mitotic spindle with a minor pool at kinetochores. In the absence of proper kinetochore-microtubule attachments, Sgo1 reinforces the Aurora B kinaseIpl1-PP1 phosphatase balance, which is critical for prolonged maintenance of the SAC response.

Liver-Secreted Extracellular Vesicles Promote Cirrhosis-Associated Skeletal Muscle Injury Through mtDNA-cGAS/STING Axis.

Skeletal muscle atrophy (sarcopenia) is a serious complication of liver cirrhosis, and chronic muscle inflammation plays a pivotal role in its pathologenesis. However, the detailed mechanism through which injured liver tissues mediate skeletal muscle inflammatory injury remains elusive. Here, it is reported that injured hepatocytes might secrete mtDNA-enriched extracellular vesicles (EVs) to trigger skeletal muscle inflammation by activating the cGAS-STING pathway. Briefly, injured liver secreted increased amounts of EVs into circulation, which are then engulfed primarily by macrophages in skeletal muscle and subsequently induce cGAS-STING signaling and its-mediated inflammatory response in muscles. In contrast, suppression of hepatic EV secretion or STING signaling significantly alleviated cirrhosis-induced skeletal muscle inflammation and muscle atrophy in vivo. Circulating EVs from cirrhotic patients showed higher levels of mtDNA, and the levels of EV-mtDNA positively correlated with the severity of liver injury. In injured hepatocytes, mitochondrial damage promoted the release of cytosolic mtDNA and the subsequent secretion of mtDNA-enriched EVs. This study reveals that injured hepatocyte-derived EVs induce skeletal muscle inflammation via the mtDNA‒STING axis, while targeted blockade of liver EV secretion or STING signaling represents a potential therapeutic approach for preventing cirrhosis-associated skeletal muscle atrophy.

A Method for Mitigating NLOS Error for UWB Based on CNN-Stacked-LSTM Model

Abstract To address the shortcomings of traditional Long Short-Term Memory (LSTM) network in Non-Line-of-Sight (NLOS) mitigation, such as the large amount of training data required and the lengthy training times, in order to enhance the model's ability to process spatial features and multi-level features, this paper proposes an NLOS mitigation method based on Stacked Long Short-Term Memory (Stacked-LSTM) network and Convolutional Neural Network (CNN). This method combines CNN and Stacked-LSTM models to efficiently extract spatial and higher-level temporal features from the Channel Impulse Response (CIR) signal, reducing the input dimension and improving the performance of the model. The constructed CNN-Stacked-LSTM model is used to mitigate NLOS errors and reduce the impact of NLOS in the original ranging data. In the model performance validation experiment, the accuracy of the CNN-Stacked-LSTM model was improved by 4%-14% compared with the CNN-LSTM, Transformer, Attention-LSTM and LSTM models, and the training time was reduced by 0.07h compared with the traditional LSTM model. The experimental results in the two actual Ultra-WideBand (UWB) environments show that compared with the other four models, the RMSE value of the CNN-Stacked-LSTM model proposed in this paper is reduced by 19.55%-58.96% and 8.64%-45.52%, respectively. It has the best mitigation effect on NLOS and the highest positioning accuracy.

HDC1 Promotes Primary Root Elongation by Regulating Auxin and K+ Homeostasis in Response to Low-K+ Stress

Plants frequently encounter relatively low and fluctuating potassium (K+) concentrations in soil, with roots serving as primary responders to this stress. Histone modifications, such as de-/acetylation, can function as epigenetic markers of stress-inducible genes. However, the signaling network between histone modifications and low-K+ (LK) response pathways remains unclear. This study investigated the regulatory role of Histone Deacetylase Complex 1 (HDC1) in primary root growth of Arabidopsis thaliana under K+ deficiency stress. Using a hdc1-2 mutant line, we observed that HDC1 positively regulated root growth under LK conditions. Compared to wild-type (WT) plants, the hdc1-2 mutant exhibited significantly inhibited primary root growth under LK conditions, whereas HDC1-overexpression lines displayed opposite phenotypes. No significant differences were observed under HK conditions. Further analysis revealed that the inhibition of hdc1-2 on root growth was due to reduced apical meristem cell proliferation rather than cell elongation. Notably, the root growth of hdc1-2 showed reduced sensitivity compared to WT after auxin treatment under LK conditions. HDC1 may regulate root growth by affecting auxin polar transport and subsequent auxin signaling, as evidenced by the altered expression of auxin transport genes. Moreover, the organ-specific RT-qPCR analyses unraveled that HDC1 negatively regulates the expression of CBL-CIPK-K+ channel-related genes such as CBL1, CBL2, CBL3, AKT1, and TPK1, thereby establishing a molecular link between histone deacetylation, auxin signaling, and CBLs-CIPKs pathway in response to K+ deficiency.

Ion Sensing via Modulation of Charge Transfer in Donor-pi-Acceptor Molecules: Structure, Mechanism & Photophysical Aspects.

This review article highlights the importance of novel charge transfer (CT) sensing approach for the detection of ions which are crucial from environmental and biological point of view. The importance, principles of charge transfer, ion sensing, its different types, and its basic process will all be covered here. The strategy has been reported with enormous sensitivity and fast signaling response owing to the fact that strong electronic connection communication exists between donor (D) and acceptor (A) part. Important discoveries made since 2010 will be examined. Herein, we will showcase the binding constants, conditions employed for sensing, and limit of detection of crucial ions via CT based sensors that researchers have bough forth for real-time applications. Additionally, the focus will be on the mechanistic aspects and signaling response as a result of the interaction between ion and sensor molecule.

Maternal Supplementation of Dietary Choline and Docosahexaenoic Acid during Gestational Nutrition Restriction Alters Hepatic mRNA and miRNA Expression Patterns in Full-Term Fetal Pigs.

Supplementing choline and docosahexaenoic acid (DHA) to pregnant gilts modified fetal pig hepatic global DNA methylation induced by gestational malnutrition, suggesting that gene expression and regulation and its associated metabolic pathways are affected in the liver of offspring during growth and development. To investigate the effect of maternal supplementation of choline, DHA and their interaction on hepatic mRNA expression, miRNA regulation and metabolic pathways in the fetal pigs born to malnourished mothers. The abundance of mRNA and miRNA was profiled in fetal liver from sows with undernutrition supplemented with choline and DHA in a 2 × 2 factorial design. The effects of choline, DHA, and their interaction on mRNA and miRNA expression were evaluated. Identification of the Biological Processes from the Gene Ontology database and miRNA Target Prediction Analysis were performed using the DAVID Functional Annotation Tool and Ingenuity Pathway Analysis. The identified miRNA-mRNA pairings were validated using RT-qPCR. 144 mRNA and 1 miRNA were altered by supplementation of choline and the alterations were associated with the inhibitions of cardiac hypertrophy signaling, IL-6 signaling, IL-3 signaling, the Th1 pathway, and the acute phase response signaling pathway. 151 mRNAs and 6 miRNAs were altered by maternal supplementation DHA and were associated with inhibition of 5 inositol-related pathways, 5 immune-related pathways, and 7 other pathways and the stimulation of PPAR signaling and RhoGDI signaling pathways. 383 mRNAs and 25 miRNAs displayed choline x DHA interactions including synergistic effects on acute phase response signaling, and antagonistic effects on tRNA splicing, PPARα/RXRα activation, and sirtuin signaling, NAD signaling and RNA polymerase I transcription pathways. 10 of the identified 20 miRNA-mRNA pairings were validated using RT-qPCR. We identified and confirmed that supplementation of choline, DHA or choline plus DHA to pregnant gilts modifies liver mRNA, miRNA, and pathways in fetal pigs during gestational undernutrition.

Combining machine learning and single-cell sequencing to identify key immune genes in sepsis

This research aimed to identify novel indicators for sepsis by analyzing RNA sequencing data from peripheral blood samples obtained from sepsis patients (n = 23) and healthy controls (n = 10). 5148 differentially expressed genes were identified using the DESeq2 technique and 5636 differentially expressed genes were identified by the limma method(|Log2 Fold Change|≥2, FDR < 0.05). A total of 1793 immune-related genes were identified from the ImmPort database, with 358 genes identified in both groups. Next, a Biological association network was constructed, and five key hub genes (CD4, HLA-DOB, HLA-DRB1, HLA-DRA, AHNAK) were identified using a combination of three topological analysis algorithms (MCC, Closeness, and MNC) and four machine learning algorithms (Random Forest, LASSO regression, SVM, and XGBoost). immune cell distribution showed that the key genes correlated with multiple immune cell infiltrations. Gene Set Enrichment Analysis (GSEA) revealed that the key genes involved multiple immune response and inflammation-related signaling pathways. Subsequently, diagnostic models were constructed using four machine learning algorithms (Logistic regression, AdaBoost, KNN, and XGBoost) based on the identified key genes. Models with the highest performance were then selected. Ultimately, single-cell sequencing data revealed that the identified key genes were expressed in various immune cells, while Quantitative PCR (qPCR) tests confirmed their reduced expression in the sepsis group.

Targeting P21-Activated Kinase 2 as a Novel Therapeutic Approach to Mitigate Endoplasmic Reticulum Stress in Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is linked to prolonged endoplasmic reticulum (ER) stress. P21-activated kinase 2 (Pak2) facilitates a protective ER stress response. This study explores the mechanism and role of Pak2 in HFpEF pathology. The HFpEF mouse model was established using a high-fat diet combined with the nitric oxide synthase inhibitor Nω-Nitro-l-arginine methyl ester (high-fat diet+Nω-Nitro-l-arginine methyl ester). The model exhibited the typical characteristics of HFpEF (cardiac hypertrophy, diastolic dysfunction with preserved systolic function, and lung edema) as determined by echocardiography and hemodynamic analysis. Terminal deoxynucleotidyl transferase dUTP nick end labeling and dihydroethidium staining results showed that cell death and reactive oxygen species generation were higher in the high-fat diet+Nω-Nitro-l-arginine methyl ester-treated group. Transmission electron microscopy revealed disruption of the ER subcellular structures in the HFpEF mouse model, while western blot analysis confirmed reduced Pak2 phosphorylation and impaired inositol-requiring enzyme 1/X-box binding protein 1 splicing ER stress response signaling. Furthermore, H9c2 cells subjected to the palmitic acid-mediated metabolic stress developed temporal changes in unfolded protein response proteins and Pak2 activity. The inositol requiring enzyme 1/X-box binding protein 1 splicing branch of unfolded protein response was impaired earlier than other branches. Overexpression of Pak2 by adenovirus in H9c2 cells sustained the activation of inositol requiring enzyme 1/X-box binding protein 1 splicing. Pak2 deficiency in the mouse heart accelerated the HFpEF progression, and this phenomenon occurred as early as 10 weeks in Pak2 cardiomyocyte-specific knockout mice. Conversely, adeno-associated virus serotype 9-mediated Pak2 overexpression mitigated HFpEF symptoms, underscoring its protective role against HFpEF progression. Pak2 prevents HFpEF progression, exerting cardioprotective effects against ER stress. These insights underscore the therapeutic value of Pak2 in HFpEF.

Unidirectional and bidirectional causation between smoking and blood DNA methylation: evidence from twin-based Mendelian randomisation.

Cigarette smoking is associated with numerous differentially-methylated genomic loci in multiple human tissues. These associations are often assumed to reflect the causal effects of smoking on DNA methylation (DNAm), which may underpin some of the adverse health sequelae of smoking. However, prior causal analyses with Mendelian Randomisation (MR) have found limited support for such effects. Here, we apply an integrated approach combining MR with twin causal models to examine causality between smoking and blood DNAm in the Netherlands Twin Register (N = 2577). Analyses revealed potential causal effects of current smoking on DNAm at > 500 sites in/near genes enriched for functional pathways relevant to known biological effects of smoking (e.g., hemopoiesis, cell- and neuro-development, and immune regulation). Notably, we also found evidence of reverse and bidirectional causation at several DNAm sites, suggesting that variation in DNAm at these sites may influence smoking liability. Seventeen of the loci with putative effects of DNAm on smoking showed highly specific enrichment for gene-regulatory functional elements in the brain, while the top three sites annotated to genes involved in G protein-coupled receptor signalling and innate immune response. These novel findings are partly attributable to the analyses of current smoking in twin models, rather than lifetime smoking typically examined in MR studies, as well as the increased statistical power achieved using multiallelic/polygenic scores as instrumental variables while controlling for potential horizontal pleiotropy. This study highlights the value of twin studies with genotypic and DNAm data for investigating causal relationships of DNAm with health and disease.

Laminaran potentiates cGAS-STING signaling to enhance antiviral responses.

Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) signaling pathway, an essential element in the innate antiviral immune responses, has emerged as a key component of innate immune system to modulate type I IFNs production and response by recognizing both exogenous and endogenous DNA. Although some cGAS-STING signaling small molecule agonists have been developed, there are few natural polysaccharides reported to activate cGAS-STING signaling for the treatment of infectious diseases. Here, we reported that Laminaran, a low molecular weight β-glucan storage polysaccharide present in brown algae, potentiates cGAS-STING signaling to promote type I IFNs production and antiviral response. Laminaran enhanced cGAS-STING signaling mediated type I IFNs production and response both in human and murine cells upon HSV-1 infection or DNA mimics stimulation. Importantly, we found that Laminaran markedly inhibited Herpes simplex virus-1 (HSV-1) induced death and inflammatory responses and increased the induction of type I IFNs in C57BL/6J mice. Mechanistically, we found Laminaran inhibited autophagy and suppressed STING autophagic degradation to positively regulate cGAS-STING signaling response. Taken together, we uncovered the function of Laminaran in DNA triggered innate immunity by enhancing cGAS-STING signaling response. Laminaran might be a potential therapeutic candidate for viral infectious diseases.

A molecularly imprinted ratio fluorescence sensor based on metal-enhanced fluorescence of core-shell structure CaF2-silver nanoparticle for visual detection of dicamba.

Although fluorescence analysis methods are widely used in pesticide residue detection, improving their sensitivity and selectivity remains a challenge. This paper presents a novel ratio fluorescence sensor based on the molecular imprinting polymers (MIPs) and metal-enhanced fluorescence for visual detection of dicamba (DIC). Calcium fluoride (CaF2) quantum dots (QDs) were immobilized on the surface of Ag@MIPs, resulting in a blue fluorescence response signal (Ag@MIPs-CaF2). The MIPs shell, which possesses a specific recognition capability, serves as an isolation layer to adjust the distance between Ag nanoparticles and CaF2 QDs for enhancing the fluorescence of CaF2 QDs by up to 7.1 times under optimal conditions. In the presence of DIC, the blue fluorescence was selectively quenched, while the reference signal red fluorescence from cadmium telluride QDs coated with silicon dioxide (CdTe@SiO2) remained relatively stable, resulting in a color change from blue to red. The sensor had a detection limit of 0.16μM for DIC in the range of 1.0 to 50.0μM, recovery rates of 85.4 to 103.5% for actual samples, and an imprinting factor of 3.28. The 3D finite-difference time-domain simulation revealed that the fluorescence enhancement was due to the local electric field amplification. Therefore, the developed sensing system in this work offers a broad application prospect for visual detection of DIC in food samples.

LMAN2 interacts with HEATR3 to expedite HER2-positive breast cancer advancement and inflammation and Akt/ERK/NF-κB signaling.

The paper aimed to reveal the impacts and the possible mechanism of action of lectin mannose-binding 2 protein (LMAN2) in HER2-positive breast cancer (BC). The expression, prognostic potential of LMAN2, and the correlation between LMAN2 and HEAT repeat containing 3 (HEATR3) in BC were analyzed in TCGA database. Intact, Mentha, and BioGrid databases predicted LMAN2-HEATR3 interactions. Reverse transcription-quantitative PCR and Western blot examined LMAN2 expression. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining, wound healing, and transwell assays, respectively, detected the aggressive cellular biological behaviors including proliferation, migration, and invasion. Western blot analyzed the expression of matrix metalloproteinases, HEATR3, and protein kinase B (Akt)/extracellular signal-regulated kinase (ERK)/nuclear factor-kappaB (NF-κB) signaling-related proteins. Co-immunoprecipitation assay was used to prove the relationship of LMAN2 with HEATR3. Enzyme-linked immunosorbent assay detected inflammatory cytokine levels. LMAN2 was overexpressed in HER2-positive BC tissues and cells and indicated unfavorable prognosis of BC patients. LMAN2 knockdown suppressed HER2-positive BC cell proliferation, migration, and invasion. LMAN2 interacted with and had a positive correlation with HEATR3. HEATR3 up-regulation reversed the repressive role of LMAN2 interference in the progression of HER2-positive BC, Akt/ERK/NF-κB signaling, and inflammatory response. Altogether, LMAN2 silencing might exert anti-tumor and anti-inflammatory properties and inactivate Akt/ERK/NF-κB signaling in HER2-positive BC via binding to HEATR3.

Operando Photoelectrochemical Surface-Enhanced Raman Spectroscopy: Interfacial Mechanistic Insights and Simultaneous Detection of Patulin.

Comprehending the biosensing mechanism of the biosensor interface is crucial for sensor development, yet accurately reflecting interfacial interactions within actual detection environments remains an unsolved challenge. An operando photoelectrochemical surface-enhanced Raman spectroscopy (PEC-SERS) biosensing platform was developed, capable of simultaneously capturing photocurrent and SERS signals, allowing operando characterization of the interfacial biosensing behavior. Porphyrin-based MOFs (Zr-MOF) served as bifunctional nanotags, providing a photocurrent and stable Raman signal output under 532 nm laser irradiation. Aptamer was used to bridge the Zr-MOF and the silver-encased gold nanodumbbells (AuNDs@AgNPs). The simultaneous in situ acquisition of target-induced PEC and SERS signal responses facilitated the correlation of electron transfer information from the photocurrent with the distance information from the SERS signal. It revealed the biosensing mechanism in which target-induced aptamer conformational bending drove the Zr-MOF to approach the electrode. However, the increase in charge transfer observed through conventional electrochemical methods contradicts the conclusions drawn from the operando PEC-SERS analysis. Comprehensive analysis indicated that redox probes introduced during the non-in-situ measurement process became adsorbed within the MOF pores, potentially affecting the judgment of the biosensing mechanism. In addition, the operando PEC-SERS biosensor simultaneously obtained two independent signals, providing self-verification to improve the accuracy and reliability of patulin detection. The linear ranges were 1 pg mL-1-10 ng mL-1 for the PEC method and 1 pg mL-1-100 ng mL-1 for the SERS method, respectively. This work provides a powerful tool for determining the interface characteristics of biosensors.