Paraventricular Thalamus Dynamically Modulates Aversive Memory via Tuning Prefrontal Inhibitory Circuitry.

The impact of stress on the formation and expression of memory is well studied, especially on the contributions of stress hormones. But how stress affects brain circuitry dynamically to modulate memory is far less understood. Here, we used male C57BL6/J mice in an auditory fear conditioning as a model system to examine this question and focused on the impact of stress on dorsomedial prefrontal cortex (dmPFC) neurons which play an important role in probabilistic fear memory. We found that paraventricular thalamus (PVT) neurons are robustly activated by acute restraining stress. Elevated PVT activity during probabilistic fear memory expression increases spiking in the dmPFC somatostatin neurons which in turn suppresses spiking of dmPFC parvalbumin (PV) neurons, and reverts the usual low fear responses associated with probabilistic fear memory to high fear. This dynamic and reversible modulation allows the original memory to be preserved and modulated during memory expression. In contrast, elevated PVT activity during fear conditioning impairs synaptic modifications in the dmPFC PV-neurons and abolishes the formation of probabilistic fear memory. Thus, PVT functions as a stress sensor to modulate the formation and expression of aversive memory by tuning inhibitory functions in the prefrontal circuitry.SIGNIFICANCE STATEMENT The impact of stress on cognitive functions, such as memory and executive functions, are well documented especially on the impact by stress hormone. However, the contributions of brain circuitry are far less understood. Here, we show that a circuitry-based mechanism can dynamically modulate memory formation and expression, namely, higher stress-induced activity in paraventricular thalamus (PVT) impairs the formation and expression of probabilistic fear memory by elevating the activity of somatostatin-neurons to suppress spiking in dorsomedial prefrontal parvalbumin (PV) neurons. This stress impact on memory via dynamic tuning of prefrontal inhibition preserves the formed memory but enables a dynamic expression of memory. These findings have implications for better stress coping strategies as well as treatment options including better drug targets/mechanisms.

Advances and optimization strategies in bacteriophage therapy for treating inflammatory bowel disease.

In the advancement of Inflammatory Bowel Disease (IBD) treatment, existing therapeutic methods exhibit limitations; they do not offer a complete cure for IBD and can trigger adverse side effects. Consequently, the exploration of novel therapies and multifaceted treatment strategies provides patients with a broader range of options. Within the framework of IBD, gut microbiota plays a pivotal role in disease onset through diverse mechanisms. Bacteriophages, as natural microbial regulators, demonstrate remarkable specificity by accurately identifying and eliminating specific pathogens, thus holding therapeutic promise. Although clinical trials have affirmed the safety of phage therapy, its efficacy is prone to external influences during storage and transport, which may affect its infectivity and regulatory roles within the microbiota. Improving the stability and precise dosage control of bacteriophages-ensuring robustness in storage and transport, consistent dosing, and targeted delivery to infection sites-is crucial. This review thoroughly explores the latest developments in IBD treatment and its inherent challenges, focusing on the interaction between the microbiota and bacteriophages. It highlights bacteriophages' potential as microbiome modulators in IBD treatment, offering detailed insights into research on bacteriophage encapsulation and targeted delivery mechanisms. Particular attention is paid to the functionality of various carrier systems, especially regarding their protective properties and ability for colon-specific delivery. This review aims to provide a theoretical foundation for using bacteriophages as microbiome modulators in IBD treatment, paving the way for enhanced regulation of the intestinal microbiota.

Comprehensive analysis of clinical data and radiomic features from contrast enhanced CT for differentiating benign and malignant pancreatic intraductal papillary mucinous neoplasms.

The primary aim of this investigation was to leverage radiomics features derived from contrast-enhanced abdominal computed tomography (CT) scans to devise a predictive model to discern the benign and malignant nature of intraductal papillary mucinous neoplasms (IPMNs). Radiomic signatures were meticulously crafted to delineate benign from malignant IPMNs by extracting pertinent features from contrast-enhanced CT images within a designated training cohort (n = 84). Subsequent validation was conducted with data from an independent test cohort (n = 37). The discriminative ability of the model was quantitatively evaluated through receiver operating characteristic (ROC) curve analysis, with the integration of carefully selected clinical features to improve the comparative analysis. Arterial-phase images were utilized to construct a model comprising 8 features for distinguishing between benign and malignant cases. The model achieved an accuracy of 0.891 [95% confidence interval (95% CI), 0.816-0.996] in the cross-validation set and 0.553 (95% CI 0.360-0.745) in the test set. Conversely, employing 9 features from the venous-phase resulted in a model with a cross-validation accuracy of 0.862 (95%CI 0.777-0.946) and a test set accuracy of 0.801 (95% CI 0.653-0.950).Integrating the identified clinical features with imaging features yielded a model with a cross-validation accuracy of 0.934 (95% CI 0.879-0.990) and a test set accuracy of 0.904 (95% CI 0.808-0.999), thereby further improving its discriminatory ability. Our findings distinctly illustrate that venous-phase radiomics features eclipse arterial-phase radiomic features in terms of predictive accuracy regarding the nature of IPMNs. Furthermore, the synthesis and meticulous screening of clinical features with radiomic data significantly increased the diagnostic efficacy of our model, underscoring the pivotal importance of a comprehensive and integrated approach for accurate risk stratification in IPMN management.

Advancements and challenges in oncolytic virus therapy for gastrointestinal tumors.

BACKGROUND: Tumors of the gastrointestinal tract impose a substantial healthcare burden due to their prevalence and challenging prognosis. METHODS: We conducted a review of peer-reviewed scientific literature using reputable databases (PubMed, Scopus, Web of Science) with a focus on oncolytic virus therapy within the context of gastrointestinal tumors. Our search covered the period up to the study's completion in June 2023. INCLUSION AND EXCLUSION CRITERIA: This study includes articles from peer-reviewed scientific journals, written in English, that specifically address oncolytic virus therapy for gastrointestinal tumors, encompassing genetic engineering advances, combined therapeutic strategies, and safety and efficacy concerns. Excluded are articles not meeting these criteria or focusing on non-primary gastrointestinal metastatic tumors. RESULTS: Our review revealed the remarkable specificity of oncolytic viruses in targeting tumor cells and their potential to enhance anti-tumor immune responses. However, challenges related to safety and efficacy persist, underscoring the need for ongoing research and improvement. CONCLUSION: This study highlights the promising role of oncolytic virus therapy in enhancing gastrointestinal tumor treatments. Continued investigation and innovative combination therapies hold the key to reducing the burden of these tumors on patients and healthcare systems.

Phage-based peptides for pancreatic cancer diagnosis and treatment: alternative approach.

Pancreatic cancer is a devastating disease with a high mortality rate and a lack of effective therapies. The challenges associated with early detection and the highly aggressive nature of pancreatic cancer have limited treatment options, underscoring the urgent need for better disease-modifying therapies. Peptide-based biotherapeutics have become an attractive area of research due to their favorable properties such as high selectivity and affinity, chemical modifiability, good tissue permeability, and easy metabolism and excretion. Phage display, a powerful technique for identifying peptides with high affinity and specificity for their target molecules, has emerged as a key tool in the discovery of peptide-based drugs. Phage display technology involves the use of bacteriophages to express peptide libraries, which are then screened against a target of interest to identify peptides with desired properties. This approach has shown great promise in cancer diagnosis and treatment, with potential applications in targeting cancer cells and developing new therapies. In this comprehensive review, we provide an overview of the basic biology of phage vectors, the principles of phage library construction, and various methods for binding affinity assessment. We then describe the applications of phage display in pancreatic cancer therapy, targeted drug delivery, and early detection. Despite its promising potential, there are still challenges to be addressed, such as optimizing the selection process and improving the pharmacokinetic properties of phage-based drugs. Nevertheless, phage display represents a promising approach for the development of novel targeted therapies in pancreatic cancer and other tumors.

Triggering "signal-on" photoelectrochemical responses by heterojunction transition for selective detection of copper(II) based on Pd/MoS2@g-C3N4 nanocomposites.

Controlling the concentration of copper(II) in aquatic systems is of importance for human health. Numerous traditional technologies to detect Cu2+ may encounter with limitations, such as high signal background and complicated operation. Herein, a highly selective photoelectrochemical (PEC) sensor is proposed for the "signal-on" detection of Cu2+ employing g-C3N4 nanosheets with MoS2 and Pd quantum dots deposited (Pd/MoS2@g-C3N4). Pd/MoS2@g-C3N4 could present the enhanced photocurrents of specific responses to Cu2+ under light irradiation. MoS2 quantum dots on the sensor are agglomerated into MoS2 bulk during sensing Cu2+, forming an efficient Z-scheme heterojunction. The heterojunction transition induced photoelectrons transferring from the bulk MoS2 to g-C3N4, resulting in "signal-on" PEC responses. Such Z-scheme heterojunction has conquered the traditional heterojunction towards "signal-on" mechanism, that was further verified by band structure measurements and DMPO spin trapping ESR analysis. Photocurrent intensities increased gradually with the addition of incremental Cu2+ concentrations, achieving a detection limit of 0.21 µM and a broad linear interval range from 1 µM to 1 mM with high selectivity and stability. This work may open a new door towards the in situ construction of g-C3N4-based Z-scheme heterojunctions for the signal-on PEC sensing platform, providing wide applications in environmental monitoring and food safety.

Harnessing filamentous phages for enhanced stroke recovery.

Stroke poses a critical global health challenge, leading to substantial morbidity and mortality. Existing treatments often miss vital timeframes and encounter limitations due to adverse effects, prompting the pursuit of innovative approaches to restore compromised brain function. This review explores the potential of filamentous phages in enhancing stroke recovery. Initially antimicrobial-centric, bacteriophage therapy has evolved into a regenerative solution. We explore the diverse role of filamentous phages in post-stroke neurological restoration, emphasizing their ability to integrate peptides into phage coat proteins, thereby facilitating recovery. Experimental evidence supports their efficacy in alleviating post-stroke complications, immune modulation, and tissue regeneration. However, rigorous clinical validation is essential to address challenges like dosing and administration routes. Additionally, genetic modification enhances their potential as injectable biomaterials for complex brain tissue issues. This review emphasizes innovative strategies and the capacity of filamentous phages to contribute to enhanced stroke recovery, as opposed to serving as standalone treatment, particularly in addressing stroke-induced brain tissue damage.

Preparation of a novel non-burning polyaluminum chloride residue(PACR) compound filler and its phosphate removal mechanisms.

As an inevitable industrial by-product, polyaluminum chloride residue (PACR) will cause serious harm to the environment if directly buried and dumped. The aim of this paper was searched a new economical, environmental, and practical way of utilization for PACR. In this paper, a novel non-burning PACR compound filler was made from mainly PACR. The prepared compound filler has excellent physical properties and phosphate adsorption efficiency of up to 99.9%. Static adsorption experiments showed that the adsorption process of phosphorus by the compound filler conformed to the pseudo-second-order kinetic model and intra-particle diffusion model. Langmuir and Freundlich isotherm models described the phosphorus adsorption process well, and the maximum phosphate adsorption capacity arrived at 42.55 mg/g. The phosphate adsorption by the compound filler is a spontaneous endothermic process. The main mechanisms are ligand exchange and Lewis acid-base interactions; calcium and aluminum play important roles in the adsorption of phosphorus by the compound filler. Dynamic column experiments showed that as much as 90% of the phosphorus removal by compound filler, and the phosphorus concentration decreased from 1 to ~0.1mg/L. The results provide a new waste resource utilization method for PACR and show the good application potential of prepared compound filler in constructed wetlands.