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Depression ranks as the fourth most prevalent global disease, with suicide incidents occurring at a younger age. Sulpiride (SUL), an atypical antidepressant drug acting as a dopamine D2 receptor antagonist and possessing anti-inflammatory properties, exhibits limited ability to penetrate the blood brain barrier (BBB). This weak penetration hampers its inhibitory effect on prolactin release in the pituitary gland, consequently leading to hyperprolactinemia. In order to enhance the central nervous system efficacy of sulpiride and reduce serum prolactin levels, we covalently linked sulpiride to VPALR derived from the nuclear DNA repair protein ku70. In vivo study on depressive mice using intraperitoneal injection of VPALR-SUL demonstrated a significant increase in struggle time and total distance compared to those treated with only sulpiride while also reducing serum prolactin concentration. The pharmacokinetic study results showed that VPALR-SUL prolonged half-life and increased bioavailability. In conclusion, VPALR-SUL exhibited potential for enhancing sulpiride transport across the BBB, augmenting its antidepressant effects, and reducing serum prolactin levels. This study laid a foundation for improving sulpiride delivery and developing novel antidepressants.

The investigation of peptide drugs has become essential in the development of innovative medications for hypertension. In this study, a sensitive high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed to determine the plasma concentration and stability of the antihypertensive peptide FR-6 in rats. An isotopically labeled peptide (with an unchanged sequence) was utilized as an internal standard (IS) for validation purposes. Subsequently, this assay was employed to examine the pharmacokinetics of different administration methods (tail vein and gavage) in Sprague Dawley (SD) rats. Extracted plasma samples underwent sample preparation through methanol protein precipitation, followed by elution of FR-6 on Wondasil C18 Superb column (4.6 × 150 mm, 5 μm), using a mobile phase consisting of formic acid (0.1%) in water (A) and formic acid (0.125%)-ammonium formate (2 mM) in methanol (B). Ion pairs corresponding to FR-6 and IS were monitored via multiple reaction monitoring (MRM) under positive ion mode: m/z 400.7 → 285.1 for FR-6 and m/z 406.1 → 295.1 for IS detection respectively. The method exhibited excellent linearity with respect to FR-6 concentrations. In addition, the inter-day and intra-day precision were 0.61–6.85% and 1.76–11.75%; the inter-day and intra-day accuracy were −7.28–0.13% and −7.20–2.28%, respectively. In conclusion, the matrix effect, extraction recovery, and stability data were validated according to FDA recommended acceptance criteria for bioanalytical methods. This validated method serves as a reliable tool for determining the concentration of antihypertensive peptide FR-6, and has been successfully applied in pharmacokinetic studies involving rats.

Thrombin plays a pivotal role in blood coagulation, wound healing, and tumor metastasis. In this study, we developed a fluorescent probe (Apt15@QDs) by functionalizing quantum dots (QDs) with an aptamer 15 to specifically recognize thrombin. The aptamer Apt15 binds specifically to thrombin by adopting a G-quadruplex conformation, resulting in the formation of a binary complex that quenches the fluorescence of the probe. Analysis using the classical fluorescence quenching equations Stem-Volmer and Lineweaver-Burk revealed that the mechanism of quenching is static in nature. The established method was successfully applied for detecting thrombin in human serum samples. As shown from the results, the established method exhibited high sensitivity, with a limit of detection (LOD) of 8 nM, and possessed a wide linear range within the concentration span of 20 to 200 nM. Additionally, this method circumvented the need for intricate experimental procedures. Furthermore, it offered a short analysis time, obviated the requirement for additional reagents, and proved suitable for high-throughput analysis of biological samples. This study presents a sensitive, straightforward, and rapid approach for detecting thrombin in complex biological matrices.

Abstract Aims Recovery of blood flow is a therapeutic approach for myocardial infarction but paradoxically induces injury to the myocardium. Exosomes (exos) are pivotal mediators for intercellular communication that can be released by different cells and are involved in cardiovascular diseases. This study aimed to explore the possible effects and mechanisms of miR‐155‐5p loaded by serum‐derived exos in myocardial infarction reperfusion injury (MIRI). Methods and results Exos were isolated from mouse serum after induction of ischaemia reperfusion (I/R) and injected into I/R‐treated mice to assess cardiac function, infarction size, and cardiomyocyte apoptosis. Primary cardiomyocytes were transfected with miR‐155‐5p inhibitor before treatment with oxygen–glucose deprivation and re‐oxygenation (OGD/R) and exos derived from the serum of I/R‐treated mice (I/R‐Exos), in which Bcl‐2, Bax, and cleaved‐caspase‐3 levels were detected. The interactions among miR‐155‐5p, NEDD4, and CypD were evaluated. miR‐155‐5p level was evidently increased in I/R‐Exos than in exos from the serum of sham‐operated mice (P

Patients with locally advanced rectal cancer (LARC) who achieve a pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) typically have a good prognosis. An early and accurate prediction of the treatment response, i.e., whether a patient achieves pCR, could significantly help doctors make tailored plans for LARC patients. This study proposes a pipeline of pCR prediction using a combination of deep learning and radiomics analysis. Taking into consideration missing pre-nCRT magnetic resonance imaging (MRI), as well as aiming to improve the efficiency for clinical application, the pipeline only included a post-nCRT T2-weighted (T2-w) MRI. Unlike other studies that attempted to carefully find the region of interest (ROI) using a pre-nCRT MRI as a reference, we placed the ROI on a “suspicious region”, which is a continuous area that has a high possibility to contain a tumor or fibrosis as assessed by radiologists. A deep segmentation network, termed the two-stage rectum-aware U-Net (tsraU-Net), is designed to segment the ROI to substitute for a time-consuming manual delineation. This is followed by a radiomics analysis model based on the ROI to extract the hidden information and predict the pCR status. The data from a total of 275 patients were collected from two hospitals and partitioned into four datasets: Seg-T (N = 88) for training the tsraUNet, Rad-T (N = 107) for building the radiomics model, In-V (N = 46) for internal validation, and Ex-V (N = 34) for external validation. The proposed method achieved an area under the curve (AUC) of 0.829 (95% confidence interval [CI]: 0.821, 0.837) on In-V and 0.815 (95% CI, 0.801, 0.830) on Ex-V. The performance of the method was considerable and stable in two validation sets, indicating that the well-designed pipeline has the potential to be used in real clinical procedures.

BackgroundAerobic glycolysis and epidermal–mesenchymal transition (EMT) play key roles in the development of bladder cancer. This study aimed to investigate the function and the underlying mechanism of dihydropyrimidinase like 2 (DPYSL2) in bladder cancer progression.MethodsThe expression pattern of DPYSL2 in bladder cancer and the correlation of DPYSL2 expression with clinicopathological characteristics of bladder cancer patients were analyzed using the data from different databases and tissue microarray. Gain- and loss-of-function assays were performed to explore the role of DPYSL2 in bladder cancer progression in vitro and in mice. Proteomic analysis was performed to identify the interacting partner of DPYSL2 in bladder cancer cells.FindingsThe results showed that DPYSL2 expression was upregulated in bladder cancer tissue compared with adjacent normal bladder tissue and in more aggressive cancer stages compared with lower stages. DPYSL2 promoted malignant behavior of bladder cancer cells in vitro, as well as tumor growth and distant metastasis in mice. Mechanistically, DPYSL2 interacted with pyruvate kinase M2 (PKM2) and promoted the conversion of PKM2 tetramers to PKM2 dimers. Knockdown of PKM2 completely blocked DPYSL2-induced enhancement of the malignant behavior, glucose uptake, lactic acid production, and epithelial–mesenchymal transition in bladder cancer cells.InterpretationIn conclusion, the results suggest that DPYSL2 promotes aerobic glycolysis and EMT in bladder cancer via PKM2, serving as a potential therapeutic target for bladder cancer treatment.

The use of flexible wearable sensors to monitor the impact of sleeping position and turning frequency on sleep and to study sleep patterns can help bedridden patients heal and recover. The flexible wearable sleeping-position monitoring device was designed and developed using a flexible angle sensor and a six-axis motion sensor to measure the dynamic changes in body posture during sleep. Based on the changes in the output parameters of the flexible angle sensor and the six-axis motion sensor, we determined the change in the subject’s lying position, verifying and analyzing the relationship between lying position preference, turning frequency, and sleep quality in healthy subjects. The sleeping-position monitoring device was worn by 13 subjects (7 males and 6 females) without sleep disorders before the sleep experiment. They performed more than 50 sleeping-position changes to ensure the accuracy of the monitoring device. Subjects slept in their beds for 8 h per night for 15 nights. During that time, they wore the sleeping-position monitoring device and a wristband sleep-monitoring bracelet on their left hand, and gathered the subjective sleep data using questionnaires. The results show that the most critical influencing factors are sleeping-position preference and frequency of turning. Data analysis reveals that subjects with a preference for right-sided lying and a lower frequency of turning had better sleep quality.

Researchers are increasingly calling for more computational thinking (CT) teaching tools and activities designed for young children. Considering young children's need to draw on their bodily experiences to learn abstract concepts, this study applied the embodied cognition perspective to design an unplugged (non-computer-based) toolkit with activities that foster CT. This study aimed to explore young children's experiences in unplugged activities. Specifically, children's perceptions about the activities were investigated, and their embodied interactions during the activities were analyzed to reveal how CT emerges as an embodied phenomenon. Results indicate that children had positive perceptions about the activities. In addition, young children's algorithmic thinking and debugging emerged most frequently. Furthermore, this study found that CT extended to both the unplugged toolkit and children's bodies and emerged in perception-action loops. This research provides insight into the instructional design of young children's CT and helps researchers understand how young children develop CT from an embodied cognition perspective.

Throughout history, progress in medicine has been intrinsically linked to the dynamics of warfare, driving innovations and transforming medical practices for the civilian population. This paper examines how World War I, characterized by the unprecedentedly large-scale utilization of trench warfare and modern mechanized weapons, catalyzed the development of medical technologies and techniques, fundamentally transforming medical practices thereafter. Key areas of medical progress discussed in this paper include facial reconstruction, vaccination for infectious diseases, mobile medical imaging, and blood preservation and transfusion, as well as their immediate and far-reaching impacts on society thereafter. Drawing upon a broad range of historical evidence such as first-hand account books, oral accounts, museum resources, and primary documents in French and English, this paper not only provides a comprehensive review of the major innovations in medical technology during World War I but also reveals the diverse personal perspectives that soldiers developed in response to the implementation of novel medical technology in that time, revealing the complex challenges associated with rapid medical and technological advancements. Overall, this paper explores the revolutionary impacts of important medical development during World War I and offers new insights into the interplay between wartime devastation and medical progress. [ABSTRACT FROM AUTHOR]