A TME-enlightened protein-binding photodynamic nanoinhibitor for highly effective oncology treatment.

The efficiency of photodynamic therapy (PDT) is greatly dependent on intrinsic features of photosensitizers (PSs), but most PSs suffer from narrow diffusion distances and short life span of singlet oxygen (1O2). Here, to conquer this issue, we propose a strategy for in situ formation of complexes between PSs and proteins to deactivate proteins, leading to highly effective PDT. The tetrafluorophenyl bacteriochlorin (FBC), a strong near-infrared absorbing photosensitizer, can tightly bind to intracellular proteins to form stable complexes, which breaks through the space-time constraints of PSs and proteins. The generated singlet oxygen directly causes the protein dysfunction, leading to high efficiency of PSs. To enable efficient delivery of PSs, a charge-conversional and redox-responsive block copolymer POEGMA-b-(PAEMA/DMMA-co-BMA) (PB) was designed to construct a protein-binding photodynamic nanoinhibitor (FBC@PB), which not only prolongs blood circulation and enhances cellular uptake but also releases FBC on demand in tumor microenvironment (TME). Meanwhile, PDT-induced destruction of cancer cells could produce tumor-associated antigens which were capable to trigger robust antitumor immune responses, facilitating the eradication of residual cancer cells. A series of experiments in vitro and in vivo demonstrated that this multifunctional nanoinhibitor provides a promising strategy to extend photodynamic immunotherapy.

Subgraph extraction and graph representation learning for single cell Hi-C imputation and clustering.

Single-cell Hi-C (scHi-C) technology enables the investigation of 3D chromatin structure variability across individual cells. However, the analysis of scHi-C data is challenged by a large number of missing values. Here, we present a scHi-C data imputation model HiC-SGL, based on Subgraph extraction and graph representation learning. HiC-SGL can also learn informative low-dimensional embeddings of cells. We demonstrate that our method surpasses existing methods in terms of imputation accuracy and clustering performance by various metrics.

The lncRNA LINC01605 promotes the progression of pancreatic ductal adenocarcinoma by activating the mTOR signaling pathway.

BACKGROUND: This study investigated the molecular mechanism of long intergenic non-protein coding RNA 1605 (LINC01605) in the process of tumor growth and liver metastasis of pancreatic ductal adenocarcinoma (PDAC). METHODS: LINC01605 was filtered out with specificity through TCGA datasets (related to DFS) and our RNA-sequencing data of PDAC tissue samples from Renji Hospital. The expression level and clinical relevance of LINC01605 were then verified in clinical cohorts and samples by immunohistochemical staining assay and survival analysis. Loss- and gain-of-function experiments were performed to estimate the regulatory effects of LINC01605 in vitro. RNA-seq of LINC01605-knockdown PDAC cells and subsequent inhibitor-based cellular function, western blotting, immunofluorescence and rescue experiments were conducted to explore the mechanisms by which LINC01605 regulates the behaviors of PDAC tumor cells. Subcutaneous xenograft models and intrasplenic liver metastasis models were employed to study its role in PDAC tumor growth and liver metastasis in vivo. RESULTS: LINC01605 expression is upregulated in both PDAC primary tumor and liver metastasis tissues and correlates with poor clinical prognosis. Loss and gain of function experiments in cells demonstrated that LINC01605 promotes the proliferation and migration of PDAC cells in vitro. In subsequent verification experiments, we found that LINC01605 contributes to PDAC progression through cholesterol metabolism regulation in a LIN28B-interacting manner by activating the mTOR signaling pathway. Furthermore, the animal models showed that LINC01605 facilitates the proliferation and metastatic invasion of PDAC cells in vivo. CONCLUSIONS: Our results indicate that the upregulated lncRNA LINC01605 promotes PDAC tumor cell proliferation and migration by regulating cholesterol metabolism via activation of the mTOR signaling pathway in a LIN28B-interacting manner. These findings provide new insight into the role of LINC01605 in PDAC tumor growth and liver metastasis as well as its value for clinical approaches as a metabolic therapeutic target in PDAC.

Microglial LRRK2-mediated NFATc1 attenuates α-synuclein immunotoxicity in association with CX3CR1-induced migration and the lysosome-initiated degradation.

Synucleinopathies refer to a range of neurodegenerative diseases caused by abnormal α-synuclein (α-Syn) deposition, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Their pathogenesis is strongly linked to microglial dysfunction and neuroinflammation, which involves the leucine-rich-repeat kinase 2 (LRRK2)-regulated nuclear factor of activated T-cells (NFAT). Of the NFAT family, NFATc1 has been found to be increasingly translocated into the nucleus in α-syn stimulation. However, the specific role of NFATc1-mediated intracellular signaling in PD remains elusive in regulating microglial functions. In the current study, we crossbred LRRK2 or NFATc1 conditional knockout mice with Lyz2Cre mice to generate mice with microglia-specific deletion of LRRK2 or NFATc1, and by stereotactic injection of fibrillary α-Syn, we generated PD models in these mice. We found that LRRK2 deficiency enhanced microglial phagocytosis in the mice after α-Syn exposure and that genetic inhibition of NFATc1 markedly diminished phagocytosis and α-Syn elimination. We further demonstrated that LRRK2 negatively regulated NFATc1 in α-Syn-treated microglia, in which microglial LRRK2-deficiency facilitated NFATc1 nuclear translocation, CX3CR1 upregulation, and microglia migration. Additionally, NFATc1 translocation upregulated the expression of Rab7 and promoted the formation of late lysosomes, resulting in α-Syn degradation. In contrast, the microglial NFATc1 deficiency impaired CX3CR1 upregulation and the formation of Rab7-mediated late lysosomes. These findings highlight the critical role of NFATc1 in modulating microglial migration and phagocytosis, in which the LRRK2-NFATc1 signaling pathway regulates the expression of microglial CX3CR1 and endocytic degradative Rab7 to attenuate α-synuclein immunotoxicity.

Analysis of cuproptosis-related lncRNA signature for predicting prognosis and tumor immune microenvironment in pancreatic cancer.

Pancreatic cancer (PC) is a highly malignant digestive tract tumor, with a dismal 5-year survival rate. Recently, cuproptosis was found to be copper-dependent cell death. This work aims to establish a cuproptosis-related lncRNA signature which could predict the prognosis of PC patients and help clinical decision-making. Firstly, cuproptosis-related lncRNAs were identified in the TCGA-PAAD database. Next, a cuproptosis-related lncRNA signature based on five lncRNAs was established. Besides, the ICGC cohort and our samples from 30 PC patients served as external validation groups to verify the predictive power of the risk signature. Then, the expression of CASC8 was verified in PC samples, scRNA-seq dataset CRA001160, and PC cell lines. The correlation between CASC8 and cuproptosis-related genes was validated by Real-Time PCR. Additionally, the roles of CASC8 in PC progression and immune microenvironment characterization were explored by loss-of-function assay. As showed in the results, the prognosis of patients with higher risk scores was prominently worse than that with lower risk scores. Real-Time PCR and single cell analysis suggested that CASC8 was highly expressed in pancreatic cancer and related to cuproptosis. Additionally, gene inhibition of CASC8 impacted the proliferation, apoptosis and migration of PC cells. Furthermore, CASC8 was demonstrated to impact the expression of CD274 and several chemokines, and serve as a key indicator in tumor immune microenvironment characterization. In conclusion, the cuproptosis-related lncRNA signature could provide valuable indications for the prognosis of PC patients, and CASC8 was a candidate biomarker for not only predicting the progression of PC patients but also their antitumor immune responses.

Emergence and clonal dissemination of KPC-3-producing Pseudomonas aeruginosa in China with an IncP-2 megaplasmid.

BACKGROUND: Despite the global prevalence of Klebsiella pneumoniae Carbapenemase (KPC)-type class A ß-lactamases, occurrences of KPC-3-producing isolates in China remain infrequent. This study aims to explore the emergence, antibiotic resistance profiles, and plasmid characteristics of blaKPC-3-carrying Pseudomonas aeruginosa. METHODS: Species identification was performed by MALDI-TOF-MS, and antimicrobial resistance genes (ARGs) were identified by polymerase chain reaction (PCR). The characteristics of the target strain were detected by whole-genome sequencing (WGS) and antimicrobial susceptibility testing (AST). Plasmids were analyzed by S1-nuclease pulsed-field gel electrophoresis(S1-PFGE), Southern blotting and transconjugation experiment. RESULTS: Five P. aeruginosa strains carrying blaKPC-3 were isolated from two Chinese patients without a history of travelling to endemic areas. All strains belonged to the novel sequence type ST1076. The blaKPC-3 was carried on a 395-kb IncP-2 megaplasmid with a conserved structure (IS6100-ISKpn27-blaKPC-3-ISKpn6-korC-klcA), and this genetic sequence was identical to many plasmid-encoded KPC of Pseudomonas species. By further analyzing the genetic context, it was supposed that the original of blaKPC-3 in our work was a series of mutation of blaKPC-2. CONCLUSIONS: The emergence of a multidrug resistance IncP-2 megaplasmid and clonal transmission of blaKPC-3-producing P. aeruginosa in China underlined the crucial need for continuous monitoring of blaKPC-3 for prevention and control of its further dissemination in China.

ADAMTS12 promotes migration and epithelial-mesenchymal transition and predicts poor prognosis for pancreatic cancer.

BACKGROUND: ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family, a group of extracellular multifunctional enzymes, has been proven to play a pivotal role in the tumor. In pancreatic cancer, the role and mechanism of this family remain unclear. The present study aimed to figure out the hub gene of ADAMTSs and explore the exact roles in the prognosis and biological functions in pancreatic ductal adenocarcinoma (PDAC). METHODS: We used several databases to analyze the ADAMTS family and then screen out the hub genes. The expression of ADAMTS12 in 106 pairs of PDAC tumors and adjacent normal tissues was examined by immunohistochemistry, and its correlations with clinical parameters were further analyzed. The impacts of ADAMTS12 on the migration of PDAC cells were predicted by gene set enrichment analysis and confirmed by transwell assays. The potential impacts of ADAMTS12 on the epithelial-mesenchymal transition (EMT) were identified by database analysis and experimental proof of real-time quantitative polymerase chain reaction (qPCR) and Western blotting. RESULTS: Our study found that ADAMTS12 was a crucial gene in PDAC, and it was highly expressed in tumor tissues when compared to that in the adjacent tissues. ADATMS12 had predictive value of a poor prognosis for PDAC. The elevation of ADAMTS12 was parallel to the progression of PDAC. Inhibition of ADAMTS12 suppressed the migration of PDAC cells and interfered with the process of EMT. CONCLUSIONS: ADAMTS12 is a crucial member of ADAMTSs in PDAC and a predictor of poor prognosis. Additionally, based on its impacts on migration and metastasis in PDAC and the relationship with EMT, ADAMTS12 plays a role of an oncogene in PDAC and may be a promising target for treatment.

Microfluidic flow cytometry for blood-based biomarker analysis.

Flow cytometry has proven its capability for rapid and quantitative analysis of individual cells and the separation of targeted biological samples from others. The emerging microfluidics technology makes it possible to develop portable microfluidic diagnostic devices for point-of-care testing (POCT) applications. Microfluidic flow cytometry (MFCM), where flow cytometry and microfluidics are combined to achieve similar or even superior functionalities on microfluidic chips, provides a powerful single-cell characterisation and sorting tool for various biological samples. In recent years, researchers have made great progress in the development of the MFCM including focusing, detecting, and sorting subsystems, and its unique capabilities have been demonstrated in various biological applications. Moreover, liquid biopsy using blood can provide various physiological and pathological information. Thus, biomarkers from blood are regarded as meaningful circulating transporters of signal molecules or particles and have great potential to be used as non (or minimally)-invasive diagnostic tools. In this review, we summarise the recent progress of the key subsystems for MFCM and its achievements in blood-based biomarker analysis. Finally, foresight is offered to highlight the research challenges faced by MFCM in expanding into blood-based POCT applications, potentially yielding commercialisation opportunities.

A QoS Prediction Approach Based on Truncated Nuclear Norm Low-Rank Tensor Completion.

With the rise of mobile edge computing (MEC), mobile services with the same or similar functions are gradually increasing. Usually, Quality of Service (QoS) has become an indicator to measure high-quality services. In the real MEC service invocation environment, due to time and network instability factors, users' QoS data feedback results are limited. Therefore, effectively predicting the Qos value to provide users with high-quality services has become a key issue. In this paper, we propose a truncated nuclear norm Low-rank Tensor Completion method for the QoS data prediction. This method represents complex multivariate QoS data by constructing tensors. Furthermore, the truncated nuclear norm is introduced in the QoS data tensor completion in order to mine the correlation between QoS data and improve the prediction accuracy. At the same time, the general rate parameter is introduced to control the truncation degree of tensor mode. Finally, the prediction approximate tensor is obtained by the Alternating Direction Multiplier Method iterative optimization algorithm. Numerical experiments are conducted based on the public QoS dataset WS-Dream. The results indicate that our QoS prediction method has better prediction accuracy than other methods under different missing density QoS data.

Multi-scroll hidden attractor in memristive HR neuron model under electromagnetic radiation and its applications.

This paper aims to propose a novel no-equilibrium Hindmarsh-Rose (HR) neuron model with memristive electromagnetic radiation effect. Compared with other memristor-based HR neuron models, the uniqueness of this memristive HR neuron model is that it can generate multi-scroll hidden attractors with sophisticated topological structures and the parity of the scrolls can be controlled conveniently with changing the internal parameters of the memristor. In particular, the number of scrolls of the multi-scroll hidden attractors is also associated with the intensity of external electromagnetic radiation stimuli. The complex dynamics is numerically studied through phase portraits, bifurcation diagrams, Lyapunov exponents, and a two-parameter diagram. Furthermore, hardware circuit experiments are carried out to demonstrate theoretical analyses and numerical simulations. From the perspective of engineering application, a pseudo-random number generator is designed. Besides, an image encryption application and security analysis are also performed. The obtained results show that the memristive HR neuron model possesses excellent randomness and high security, which is suitable for chaos-based real-world applications.

High-Temperature Cyclic Oxidation Behavior and Microstructure Evolution of W- and Ce-Containing 18Cr-Mo Type Ferritic Stainless Steel.

Due to the recurrent starting and stopping operations of automobiles during service, their engines' hot ends are continually subjected to high-temperature cyclic oxidation. Therefore, it is crucial to develop ferritic stainless steels with better high-temperature oxidation resistance. This study focuses on improving the high-temperature cyclic oxidation performance of 18Cr-Mo (444-type) ferritic stainless steel by alloying with high-melting-point metal W and the rare earth element Ce. For this purpose, a high-temperature cyclic oxidation experiment was designed to simulate the actual service environment and investigate the high-temperature cyclic oxidation behavior and microstructure evolution of 444-type ferritic stainless steel alloyed with W and Ce. The oxide structure and composition formed during this process were analyzed and characterized using scanning electron microscopy/energy dispersive spectroscopy (SEM-EDS) and electron probe X-ray micro-analyzer (EPMA), in order to reveal the mechanism of action of W and Ce in the cyclic oxidation process. The results show that 18Cr-Mo ferritic stainless steel alloyed with W and Ce exhibits an excellent resistance to high-temperature cyclic oxidation. The element W can promote the precipitation of the Laves phase between the matrix and the oxide film, and the small-sized Laves phase can inhibit the interfacial diffusion of oxidation reaction elements and prevent the inward growth of the oxide film. The element Ce can refine oxide particles and reduce the thickness of the oxide film. CeO2 particles within the oxide film can serve as nucleation sites for the formation of oxide particles from reactive elements, and they also contribute to pinning the oxide film, thereby enhancing its adhesion.

An automated and intelligent microfluidic platform for microalgae detection and monitoring.

Microalgae not only play a vital role in the ecosystem but also hold promising commercial applications. Conventional methods of detecting and monitoring microalgae rely on field sampling followed by transportation to the laboratory for manual analysis, which is both time-consuming and laborious. Although machine learning (ML) algorithms have been introduced for microalgae detection in the laboratory, no integrated platform approach has yet emerged to enable real-time, on-site sampling and analysing. To solve this problem, here, we develop an automated and intelligent microfluidic platform (AIMP) that can offer automated system control, intelligent data analysis, and user interaction, providing an economical and portable solution to alleviate the drawbacks of conventional methods for microalgae detection and monitoring. We demonstrate the feasibility of the AIMP by detecting and classifying four microalgal species (Cosmarium, Closterium, Micrasterias, and Haematococcus Pluvialis) that exhibit varying sizes (from a few to hundreds of microns) and morphologies. The trained microalgae species detection network (MSDN, based on YOLOv5 architecture) achieves a high overall mean average precision at 0.5 intersection-over-union (mAP@0.5) of 92.8%. Furthermore, the versatility of the AIMP is demonstrated by long-term monitoring of astaxanthin production from Haematococcus Pluvialis over a period of 30 days. The AIMP achieved 97.5% accuracy in the detection of Haematococcus Pluvialis and 96.3% in further classification based on astaxanthin accumulation. This study opens up a new path towards microalgae detection and monitoring using portable intelligent devices, providing new ideas to accelerate progress in the ecological studies and commercial exploitation of microalgae.

A dual-enzyme-like photosensitive nanozyme for remodeling the tumor immunosuppressive microenvironment to enhance immunotherapy.

In "immune-cold" tumors, the upregulation of immunosuppressive cells and insufficient infiltration of lymphocytes contribute to the resistance against immune therapy. Herein, we have developed a dual-enzyme-like photosensitive nanozyme (PBAF) to remodel the tumor immunosuppressive microenvironment (TIME) and induce the tumor infiltration of cytotoxic T lymphocytes (CTLs). Specifically, PBAF exhibits peroxidase (POD)-like activity and glutathione oxidase (GSHOx)-like activity and can be stimulated by 750 nm laser, promoting oxidative stress at the tumor site. Consequently, this process further leads to the reconstruction of TIME in animal experiments, inducing tumor-associated macrophages (TAMs) toward the immunostimulatory M1 phenotype, eliminating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Simultaneously, PBAF also promotes dendritic cells (DCs) maturation to enhance CTLs infiltration into the tumor. The remodeled TIME and enhanced immune responses by PBAF demonstrate significant post-administration inhibition of recurrence and metastasis in the treatment of malignant tumors.

Characterization of an NDM-1-Producing Citrobacter koseri Isolate from China.

Purpose: The continuous rise in carbapenemase-producing Enterobacteriaceae infections is a major public health concern. However, there is limited information available on New Delhi metallo-ß-lactamase-1 (NDM-1) producing Citrobacter koseri. In this study, we isolated a blaNDM-1-carrying C. koseri from a stool sample of an inpatient. Our aim was to investigate the phenotypic and genomic features of this clinically derived carbapenem-resistant C. koseri isolate and to characterize the transmission pattern of the IncFII/IncN plasmid that carries the blaNDM-1 gene. Methods and Results: S1-PFGE, Southern blot and conjugation assay confirmed the presence of blaNDM-1 gene in a conjugative plasmid. C. koseri L2395 and transconjugant L2395-EC600 strains showed similar resistance spectrum. Whole-genome analysis revealed that pL2395_NDM is an IncFII/IncN plasmid with a length of 67,839 bp. Moreover, blaNDM-1 gene was found encoded in the ISKpn19-blaNDM-1-ble-tnpF-dsbD-cutA-ISKpn19 cassette array. Phylogenetic analysis revealed that strain L2395 was close to an IMP-4-bearing C. koseri from Australia. Conclusion: Ongoing surveillance will be essential to control and prevent the spread of carbapenem-resistant Citrobacter spp. in the future.

Synchronous monitoring of brain-heart electrophysiology using heart rate variability coupled with rapid quantitative electroencephalography in orthostatic hypotension patients with α-synucleinopathies: Rapid prediction of orthostatic hypotension and preliminary exploration of brain stimulation therapy.

BACKGROUND: In α-synucleinopathies, the dysfunction of the autonomic nervous system which typically manifests as orthostatic hypotension (OH) often leads to severe consequences and poses therapeutic challenges. This study aims to discover the brain-cardiac electrophysiological changes in OH patients with α-synucleinopathies using the rapid quantitative electroencephalography (qEEG) coupled with heart rate variability (HRV) technique to identify rapid, noninvasive biomarkers for early warning and diagnosis, as well as shed new light on complementary treatment approaches such as brain stimulation targets. METHODS: In this study, 26 subjects of α-synucleinopathies with OH (α-OH group), 21 subjects of α-synucleinopathies without OH (α-NOH group), and 34 healthy controls (control group) were included from September 2021 to August 2023 (NCT05527067). The heart rate-blood pressure variations in supine and standing positions were monitored, and synchronization parameters of seated resting-state HRV coupled with qEEG were collected. Time-domain and frequency-domain of HRV measures as well as peak frequency and power of the brainwaves were extracted. Differences between these three groups were compared, and correlations between brain-heart parameters were analyzed. RESULTS: The research results showed that the time-domain parameters such as MxDMn, pNN50, RMSSD, and SDSD of seated resting-state HRV exhibited a significant decrease only in the α-OH group compared to the healthy control group (p < 0.05), while there was no significant difference between the α-NOH group and the healthy control group. Several time-domain and frequency-domain parameters of seated resting-state HRV were found to be correlated with the blood pressure changes within the first 5 min of transitioning from supine to standing position (p < 0.05). Differences were observed in the power of beta1 waves (F4 and Fp2) and beta2 waves (Fp2 and F4) in the seated resting-state qEEG between the α-OH and α-NOH groups (p < 0.05). The peak frequency of theta waves in the Cz region also showed a difference (p < 0.05). The power of beta2 waves in the Fp2 and F4 brain regions correlated with frequency-domain parameters of HRV (p < 0.05). Additionally, abnormal electrical activity in the alpha, theta, and beta1 waves was associated with changes in heart rate and blood pressure within the first 5 min of transitioning from supine to standing position (p < 0.05). CONCLUSION: Rapid resting-state HRV with certain time-domain parameters below normal levels may serve as a predictive indicator for the occurrence of orthostatic hypotension (OH) in patients with α-synucleinopathies. Additionally, the deterioration of HRV parameters correlates with synchronous abnormal qEEG patterns, which can provide insights into the brain stimulation target areas for OH in α-synucleinopathy patients.

Abnormal brain-heart electrophysiology in mild and severe orthostatic hypotension.

INTRODUCTION: This study investigated the changes in cardiocerebral electrophysiology in patients with mild orthostatic hypotension (MOH) and severe orthostatic hypotension (SOH) and their relationship with the severity of orthostatic hypotension, psychiatric symptoms, and cognitive dysfunction. METHODS: This study included 72 nonorthostatic hypotension (NOH), 17 with MOH, and 11 with SOH. Seated resting-state heart rate variability (HRV) and quantitative electroencephalogram parameters were synchronized and recorded. HRV measures in the time and frequency domains were analyzed, along with the peak frequency and power of the brain waves. RESULTS: Abnormal neuronal activity was found in FP1 in patients with MOH, whereas it was more widespread in FP1, FP2, and O2 in patients with SOH (P < 0.05). Cardiac and cerebral electrophysiological abnormalities were significantly associated with orthostatic hypotension severity, psychiatric symptoms, and cognitive dysfunction. CONCLUSION: Abnormal EEG activity in patients are mainly manifested in the prefrontal and occipital lobes, especially in patients with SOH. These results may help patients to better understand the mechanisms underlying orthostatic hypotension severity and psychiatric and cognitive impairment in orthostatic hypotension.

A near-infrared broad-spectrum antimicrobial nanoplatform powered by bacterial metabolic activity for enhanced antimicrobial photodynamic-immune therapy.

The emergence of antimicrobial-resistant bacterial infections poses a significant threat to public health, necessitating the development of innovative and effective alternatives to antibiotics. Photodynamic therapy (PDT) and immunotherapy show promise in combating bacteria. However, PDT's effectiveness is hindered by its low specificity to bacteria, while immunotherapy struggles to eliminate bacteria in immunosuppressive environments. In this work, we introduce an innovative near-infrared antimicrobial nanoplatform (ZFC) driven by bacterial metabolism. ZFC, comprising d-cysteine-functionalized pentafluorophenyl bacteriochlorin (FBC-Cy) coordinated with Zn2+, is designed for antimicrobial photodynamic-immune therapy (aPIT) against systemic bacterial infections. By specifically targeting bacteria via d-amino acid incorporation into bacterial surface peptidoglycans during metabolism, ZFC achieves precise bacterial clearance in wound and pulmonary infections, exhibiting an antimicrobial efficacy of up to 90 % with minimal damage to normal cells under 750 nm light. Additionally, ZFC enhances the activation of antigen-presenting cells by 3.2-fold compared to control groups. Furthermore, aPIT induced by ZFC triggers systemic immune responses and establishes immune memory, resulting in a 1.84-fold increase in antibody expression against bacterial infections throughout the body of mice. In conclusion, aPIT prompted by ZFC presents a approach to treating bacterial infections, offering a broad-spectrum solution for systemic bacterial infections. STATEMENT OF SIGNIFICANCE: The new concept demonstrated focuses on an innovative near-infrared antimicrobial nanoplatform (ZFC) for antimicrobial photodynamic-immune therapy (aPIT), highlighting its reliance on bacterial metabolism and its non-damaging effect on normal tissues. ZFC efficiently targets deep-tissue bacterial infections by harnessing bacterial metabolism, thereby enhancing therapeutic efficacy while sparing normal tissues from harm. This approach not only clears bacterial infections effectively but also induces potent adaptive immune responses, leading to the eradication of distant bacterial infections. By emphasizing ZFC's unique mechanism driven by bacterial metabolism and its tissue-sparing properties, this work underscores the potential for groundbreaking advancements in antimicrobial therapy. Such advancements hold promise for minimizing collateral damage to healthy tissues, thereby improving treatment outcomes and mitigating the threat of antimicrobial resistance. This integrated approach represents a significant progress forward in the development of next-generation antimicrobial therapies with enhanced precision and efficacy.

Identification of Atrial Transmural Conduction Inhomogeneity Using Unipolar Electrogram Morphology.

(1) Background: Structural remodeling plays an important role in the pathophysiology of atrial fibrillation (AF). It is likely that structural remodeling occurs transmurally, giving rise to electrical endo-epicardial asynchrony (EEA). Recent studies have suggested that areas of EEA may be suitable targets for ablation therapy of AF. We hypothesized that the degree of EEA is more pronounced in areas of transmural conduction block (T-CB) than single-sided CB (SS-CB). This study examined the degree to which SS-CB and T-CB enhance EEA and which specific unipolar potential morphology parameters are predictive for SS-CB or T-CB. (2) Methods: Simultaneous endo-epicardial mapping in the human right atrium was performed in 86 patients. Potential morphology parameters included unipolar potential voltages, low-voltage areas, potential complexity (long double and fractionated potentials: LDPs and FPs), and the duration of fractionation. (3) Results: EEA was mostly affected by the presence of T-CB areas. Lower potential voltages and more LDPs and FPs were observed in T-CB areas compared to SS-CB areas. (4) Conclusion: Areas of T-CB could be most accurately predicted by combining epicardial unipolar potential morphology parameters, including voltages, fractionation, and fractionation duration (AUC = 0.91). If transmural areas of CB indeed play a pivotal role in the pathophysiology of AF, they could theoretically be used as target sites for ablation.

Brain white matter changes and their associations with non-motor dysfunction in orthostatic hypotension in α-synucleinopathy: A NODDI study.

BACKGROUND: The specific non-motor symptoms associated with α-synucleinopathies, including orthostatic hypotension (OH), cognitive impairment, and emotional abnormalities, have been a subject of ongoing controversy over the mechanisms underlying the development of a vicious cycle among them. The distinct structural alterations in white matter (WM) in patients with α-synucleinopathies experiencing OH, alongside their association with other non-motor symptoms, remain unexplored. This study employs axial diffusivity and density imaging (NODDI) to investigate WM damage specific to α-synucleinopathies with concurrent OH, delivering fresh evidence to supplement our understanding of the pathogenic mechanisms and pathological rationales behind the occurrence of a spectrum of non-motor functional impairments in α-synucleinopathies. METHODS: This study recruited 49 individuals diagnosed with α-synucleinopathies, stratified into an α-OH group (n = 24) and an α-NOH group (without OH, n = 25). Additionally, 17 healthy controls were included for supine and standing blood pressure data collection, as well as neuropsychological assessments. Magnetic resonance imaging (MRI) was utilized for the calculation of NODDI parameters, and tract-based spatial statistics (TBSS) were employed to explore differential clusters. The fibers covered by these clusters were defined as regions of interest (ROI) for the extraction of NODDI parameter values and the analysis of their correlation with neuropsychological scores. RESULTS: The TBSS analysis unveiled specific cerebral regions exhibiting disparities within the α-OH group as compared to both the α-NOH group and the healthy controls. These differences were evident in clusters that indicated a decrease in the acquisition of the neurite density index (NDI), a reduction in the orientation dispersion index (ODI), and an increase in the isotropic volume fraction (FISO) (p < 0.05). The extracted values from these ROIs demonstrated significant correlations with clinically assessed differences in supine and standing blood pressure, overall cognitive scores, and anxiety-depression ratings (p < 0.05). CONCLUSION: Patients with α-synucleinopathies experiencing OH exhibit distinctive patterns of microstructural damage in the WM as revealed by the NODDI model, and there is a correlation with the onset and progression of non-motor functional impairments.

AGFG1 increases cholesterol biosynthesis by disrupting intracellular cholesterol homeostasis to promote PDAC progression.

PURPOSE: Cholesterol metabolism reprograming has been acknowledged as a novel feature of cancers. Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a high demand of cholesterol for rapid growth. The underlying mechanism of how cholesterol metabolism homestasis are disturbed in PDAC is explored. EXPERIMENTAL DESIGN: The relevance between PDAC and cholesterol was confirmed in TCGA database. The expression and clinical association were discovered in TCGA and GEO datasets. Knockdown and overexpression of AGFG1 was adopted to perform function studies. RNA sequencing, cholesterol detection, transmission electron microscope, co-immunoprecipitation, and immunofluorescence et al. were utilized to reveal the underlying mechanism. RESULTS: AGFG1 was identified as one gene positively correlated with cholesterol metabolism in PDAC as revealed by bioinformatics analysis. AGFG1 expression was then found associated with poor prognosis in PDAC. AGFG1 knockdown led to decreased proliferation of tumor cells both in vitro and in vivo. By RNA sequencing, we found AGFG1 upregulated expression leads to enhanced intracellular cholesterol biosynthesis. AGFG1 knockdown suppressed cholesterol biosynthesis and an accumulation of cholesterol in the ER. Mechanistically, we confirmed that AGFG1 interacted with CAV1 to relocate cholesterol for the proceeding of cholesterol biosynthesis, therefore causing disorders in intracellular cholesterol metabolism. CONCLUSIONS: Our study demonstrates the tumor-promoting role of AGFG1 by disturbing cholesterol metabolism homestasis in PDAC. Our study has present a new perspective on cancer therapeutic approach based on cholerstrol metabolism in PDAC.