Self-replicating DNA circuit for high-fidelity in situ imaging of T4 polynucleotide kinase activity in living cells.

Polynucleotide kinase (PNK) is a pivotal enzyme in nucleic acid metabolism and genome maintenance, and its intracellular activity is closely associated with various disease processes. However, existing methods for monitoring PNK activity in living cells are often hindered by limited sensitivity, operational complexity, and insufficient spatial resolution. Here, we present a self-replicating DNA circuit (SDC) for in situ imaging of intracellular PNK activity with high sensitivity and spatial accuracy.

Spatially constrained disulfide bond shuffling delays insulin aggregation and enhances neurotoxicity.

Disulfide bond shuffling (DBS) critically influences protein aggregation and stability, yet its spatial constraints and biological implications remain poorly understood. Here, we demonstrate that insulin undergoes DBS within an extended spatial range up to ~19 Å, generating heterogeneous crosslinked oligomers that alter aggregation pathway. While DBS products initially delay aggregation by inhibiting primary nucleation and elongation steps, they ultimately promote the formation of distinct fibrillar structures with enhanced β-sheet content.

Saikosaponin C ameliorates tau-related pathology by modulating oxidative stress and MAPK axis in Alzheimer's disease.

Ethnopharmacological Relevance: Saikosaponin C (SSc), a traditional Chinese herbal medicine, is a triterpene saponin and an active compound extracted from Radix Bupleuri. It has been demonstrated to have neuroprotective effects in cellular models of neurodegenerative diseases; however, its precise mechanism of action in alleviating tau pathology in Alzheimer's disease (AD), as well as its potential to improve cognitive deficits in animal models, has not yet been elucidated.

Aim Of The Study: In this study, we investigated the in vivo therapeutic effects of SSc on a human tau (hTau) mouse model expressing normal hTau isoforms in terms of tau-related pathology (tauopathy) and the underlying mechanisms.

High-Coverage Stereoproteome Mapping Uncovers Pervasive Protein Stereoisomerization Associated with Neurodegeneration.

Protein asymmetry, while crucial for life, can arise from subtle stereoisomerization. However, a comprehensive understanding of the breadth and specificity of the whole stereoproteome (STEP) has been hindered by insufficient stereoisomeric resolution. Here, we introduce an untargeted, STEP discovery protocol for comprehensive STEP profiling and relative quantification.

Dietary total antioxidant capacity and risk of prediabetes and diabetes mellitus: a systematic review and dose-response meta-analysis of 170,919 participants.

Background: Observational studies have assessed the association between total antioxidant capacity of the diet and risk of diabetes mellitus. However, results from these studies were not entirely consistent. In the current systematic review and dose-response meta-analysis, we aimed to determine the association between dietary total antioxidant capacity (TAC) and the risk of prediabetes and diabetes mellitus.

Zipper-interacting protein kinase mediates neuronal cell death and cognitive dysfunction in traumatic brain injury via regulating DEDD.

Neuronal cell death is a causative process in traumatic brain injury (TBI)-induced structural and functional impairment of the central nervous system. However, the upstream trigger of TBI-induced neuronal loss and the underlying molecular pathways remain unclear. Zipper-interacting protein kinase (ZIPK) has been shown to be upregulated in Alzheimer's disease and ischemic stroke and to play a role in cellular apoptosis, while its pathological significance in TBI has not been reported.

Bushen Huoxue acupuncture ameliorates Alzheimer's disease by upregulating MARCHF3 to induce NLRP3 ubiquitination and inhibit caspase-1-dependent pyroptosis.

Alzheimer's disease (AD) is a common neurodegenerative disorder that places a heavy burden on patients and society. Hippocampal neuronal loss is a hallmark of AD progression. Therefore, understanding the mechanism underlying hippocampal neuronal death would be of great importance for the diagnosis and treatment of AD.

Identification and functional validation of miR-190b-5p and miR-296-3p as novel therapeutic attenuators of liver fibrosis.

Background & Aims: Liver fibrosis and its end-stage form cirrhosis contribute to millions of deaths annually. The lack of robust antifibrotic molecules is in part attributed to the absence of any functional screens to identify molecular regulators using patient-derived primary human hepatic myofibroblasts, which are key drivers of fibrosis.

Methods: Here, to identify robust regulators of fibrosis, we performed functional microRNA screenings in primary human hepatic myofibroblasts followed by in vivo validation in three independent mouse models of fibrosis (toxin, cholestasis and MASH).

Endogenous Glutathione-Activated Nucleic Acid Molecular Circuitry for Cell-Specific MicroRNA Imaging.

Sensitive and reliable microRNA imaging in living cells has significant implications for clinical diagnosis and monitoring. Catalytic DNA circuits have emerged as potent tools for tracking these intracellular biomarkers and probing the corresponding biochemical processes. However, their utility is hindered by the low resistance to external interference, leading to undesired off-site activation and consequent signal leakage.

m6A-dependent mature miR-151-5p accelerates the malignant process of HNSCC by targeting LYPD3.

miRNA has emerged as a crucial regulator in various of pathological and physiological processes, yet its precise mechanism of action the detailed mechanism of their action in Head and neck squamous cell carcinoma (HNSCC) remains incompletely understood. This study sheds light on the role of mi-151-5p, revealing its significantly elevated expression in tumor cells, which notably enhances the invasion and migration of HNSCC cells. This effect is achieved through directly targeting LY6/PLAUR Domain Containing 3 (LYPD3) by miR-151-5p, involving complementary binding to the 3'-untranslated regions (3'-UTR) in the mRNA of LYPD3.

A Methylation-Gated DNAzyme Circuit for Spatially Controlled Imaging of MicroRNA in Cells and Animals.

Epigenetic modification plays an indispensable role in regulating routine molecular signaling pathways, yet it is rarely used to modulate molecular self-assembly networks. Herein, we constructed a bioorthogonal demethylase-stimulated DNA circuitry (DSC) system for high-fidelity imaging of microRNA (miRNA) in live cells and mice by eliminating undesired off-site signal leakage. The simple and robust DSC system is composed of a primary cell-specific circuitry regulation (CR) module and an ultimate signal-transducing amplifier (SA) module.

Direct reduction of NO into N catalyzed by fullerene-supported rhodium clusters.

Catalytic conversion of NO has long been a focus of atmospheric pollution control and diesel vehicle exhaust treatment. Rhodium is one of the most effective metals for catalyzing NO reduction, and understanding the nature of the active sites and underlying mechanisms can help improve the design of Rh-based catalysts towards NO reduction. In this work, we investigated the detailed catalytic mechanisms for the direct reduction of NO to N by fullerene-supported rhodium clusters, CRh, with density functional theory calculations.

Scaling up of a Self-Confined Catalytic Hybridization Circuit for Robust microRNA Imaging.

The precise regulation of cellular behaviors within a confined, crowded intracellular environment is highly amenable in diagnostics and therapeutics. While synthetic circuitry system through a concatenated chemical reaction network has rarely been reported to mimic dynamic self-assembly system. Herein, a catalytic self-defined circuit (CSC) for the hierarchically concatenated assembly of DNA domino nanostructures is engineered.

Lung microbiome: new insights into the pathogenesis of respiratory diseases.

The lungs were long thought to be sterile until technical advances uncovered the presence of the lung microbial community. The microbiome of healthy lungs is mainly derived from the upper respiratory tract (URT) microbiome but also has its own characteristic flora. The selection mechanisms in the lung, including clearance by coughing, pulmonary macrophages, the oscillation of respiratory cilia, and bacterial inhibition by alveolar surfactant, keep the microbiome transient and mobile, which is different from the microbiome in other organs.

Which patients with coronary artery disease should include oral nitrates on their discharge medication list?

Background: Which patients with coronary artery disease (CAD) should have oral nitrates on their discharge medication list after coronary angiography (CAG)? To assess the relationship between oral nitrates included in the discharge medication list and major adverse cardiovascular events (MACEs) among CAD patients, we designed this retrospective cohort study.

Methods: A total of 2979 CAD patients hospitalised in the Department of Cardiology, Affiliated Hospital of Jining Medical University from May 2013 to October 2015 were enrolled, grouped according to whether oral nitrates were included at discharge after CAG, and followed up for MACEs for a mean of 4.42 years after discharge.

Death-associated protein kinase 1 phosphorylates MDM2 and inhibits its protein stability and function.

Breast cancer is one of the major malignancies in women, and most related deaths are due to recurrence, drug resistance, and metastasis. The expression of the mouse double minute 2 (MDM2) oncogene is upregulated in breast cancer; however, its regulatory mechanism has yet to be fully elucidated. Herein, we identified the tumor suppressor death-associated protein kinase 1 (DAPK1) as a novel MDM2 regulator by unbiased peptide library screening.

Quantitative Proteomic and Phosphoproteomic Analyses Reveal a Role of Death-Associated Protein Kinase 1 in Regulating Hippocampal Synapse.

Death-associated protein kinase 1 (DAPK1) is a stress-responsive calcium/calmodulin (CaM)-regulated serine/threonine protein kinase that is actively involved in stress-induced cell death. The dysregulation of DAPK1 has been established in various neurological disorders such as epilepsy, Alzheimer's disease (AD), and Parkinson's disease (PD). Recent research indicates a synaptic localization of DAPK1 in neurons, suggesting a potential role of DAPK1 in modulating synaptic structure and function.

Activation of transient receptor potential vanilloid 1 ameliorates tau accumulation-induced synaptic damage and cognitive dysfunction via autophagy enhancement.

Aims: The autophagy-lysosomal pathway is important for maintaining cellular proteostasis, while dysfunction of this pathway has been suggested to drive the aberrant intraneuronal accumulation of tau protein, leading to synaptic damage and cognitive impairment. Previous studies have demonstrated that the activation of transient receptor potential vanilloid 1 (TRPV1) by capsaicin has a positive impact on cognition and AD-related biomarkers. However, the effect and mechanism of TPRV1 activation on neuronal tau homeostasis remain elusive.

A Smart Deoxyribozyme-Programmable Catalytic DNA Circuit for High-Contrast MicroRNA Imaging.

Synthetic catalytic DNA circuits have been recognized as a promising signal amplification toolbox for sensitive intracellular imaging, yet their selectivity and efficiency are always constrained by uncontrolled off-site signal leakage and inefficient on-site circuitry activation. Thus, the endogenously controllable on-site exposure/activation of DNA circuits is highly desirable for achieving the selective imaging of live cells. Herein, an endogenously activated DNAzyme strategy was facilely integrated with a catalytic DNA circuit for guiding the selective and efficient microRNA imaging in vivo.

Bioartificial liver with reprogrammed hepatocytes ready for prime time.

In this issue, Wang et al. provide evidence of the pre-clinical as well as the clinical utility of in vitro-generated directly reprogrammed human hepatocytes in bioartificial liver. This approach will help offer patients a more curative surgical therapy for liver cancer and improve survival rates.

Ablation of Death-Associated Protein Kinase 1 Changes the Transcriptomic Profile and Alters Neural-Related Pathways in the Brain.

Death-associated protein kinase 1 (DAPK1), a Ca/calmodulin-dependent serine/threonine kinase, mediates various neuronal functions, including cell death. Abnormal upregulation of DAPK1 is observed in human patients with neurological diseases, such as Alzheimer's disease (AD) and epilepsy. Ablation of DAPK1 expression and suppression of DAPK1 activity attenuates neuropathology and behavior impairments.

Early Predictors of Infected Pancreatic Necrosis in Severe Acute Pancreatitis: Implications of Neutrophil to Lymphocyte Ratio, Blood Procalcitonin Concentration, and Modified CT Severity Index.

Background: Infected pancreatic necrosis (IPN) accounts for 30% mortality in severe acute pancreatitis (SAP). Early prediction of IPN occurrence is critical for prophylactic measures to be taken. This study aimed to evaluate the predicting value for IPN of combined markers at early stages of SAP.

The compact integration of a cascaded HCR circuit for highly reliable cancer cell discrimination.

The accurate identification of multiple biomarkers involved in disease plays a vital role in effectively distinguishing cancer cells from normal cells, facilitating reliable cancer diagnosis. Motivated by this knowledge, we have engineered a compact and clamped cascaded DNA circuit for specifically discriminating cancer cells from normal cells the amplified multi-microRNA imaging strategy. The proposed DNA circuit combines the traditional cascaded DNA circuit with multiply localized responsive character through the elaboration of two super-hairpin reactants, thus concurrently streamlining the circuit components and realizing localization-intensified cascaded signal amplification.