Search Results (63)

Background: Human African trypanosomiasis (HAT), caused by Trypanosoma brucei, is a neglected tropical disease with limited treatments, highlighting the pressing need for new drugs. Cell division cycle-2-related kinase 12 (CRK12), a pivotal protein involved in the cell cycle regulation of T. brucei, has emerged as a promising therapeutic target for HAT, yet effective CRK12 inhibitors remain lacking. Methods: An integrated strategy combining computational modeling, virtual screening, molecular dynamics (MD) simulations, and experimental validation was adopted to discover potential inhibitors against CRK12. By using the predicted and refined 3D structure of CRK12 from AlphaFold2 and MD simulation, over 1.5 million compounds were screened based on multiple-scale molecular docking, and 26 compounds were selected for evaluation of biological activity based on anti-T. brucei bioassays. Dose–response curves were generated for the most potent inhibitors, and the interaction mechanism between the top four compounds and CRK12 was explored by MD simulations and MM/GBSA binding free energy analysis. Results: Of the 26 compounds, six compounds demonstrated sub-micromolar to low-micromolar IC₅₀ values (0.85–3.50 µM). The top four hits, F733-0072, F733-0407, L368-0556, and L439-0038, exhibited IC₅₀ values of 1.11, 1.97, 0.85, and 1.66 µM, respectively. Binding free energy and energy decomposition analyses identified ILE335, VAL343, PHE430, ALA433, and LEU482 as hotspot residues for compound binding. Hydrogen bonding analysis demonstrated that these compounds can form stable hydrogen bonds with the hinge residue ALA433, ensuring their stable binding within the active site. Conclusions: This study establishes a robust and cost-effective pipeline for CRK12 inhibitor discovery, identifying several novel inhibitors demonstrating promising anti-HAT activity. The newly discovered scaffolds exhibit structural diversity distinct from known CRK12 inhibitors, providing valuable lead compounds for anti-trypanosomal drug development. Full article

Multiple sclerosis (MS) is a highly disabling chronic neurological condition affecting young adults. Inflammation, demyelination, and axonal damage are key pathological features of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Our previous work demonstrated that inhibiting spermine oxidase (SMOX) with MDL72527, a selective irreversible pharmacological inhibitor, significantly reduced clinical symptoms, retinal ganglion cell (RGC) loss, and optic nerve inflammation in EAE mice. The present study explored the broader therapeutic potential of SMOX inhibition, focusing on myelin preservation, axonal integrity, and visual function in the EAE model. Electron microscopy of optic nerve cross-sections showed significant preservation of myelin thickness and axonal integrity due to SMOX inhibition. The quantitative assessment showed that g-ratio and axon count metrics were significantly improved in MDL72527-treated EAE mice compared to their vehicle-treated counterparts. Immunofluorescence studies confirmed these findings, showing increased preservation of myelin and axonal proteins in MDL72527-treated EAE mice compared to the vehicle-treated group. Functional assessment studies (Electroretinography) demonstrated significant improvement in RGC function and axonal conduction in EAE mice treated with MDL72527. Furthermore, SMOX inhibition downregulated the expression of galectin3 (Gal3), a mediator of neuroinflammation, indicating Gal3’s role in SMOX-mediated neuroprotection. This study provides compelling evidence for the potential of SMOX inhibition as a therapeutic strategy in multiple sclerosis and other demyelinating disorders. Full article

The simultaneous use of two or more drugs in clinical treatment may raise the risk of a drug–drug interaction (DDI). DDI prediction is very important to avoid adverse drug events in combination therapy. Recently, deep learning methods have been applied successfully to DDI prediction and improved prediction performance. However, there are still some problems with the present models, such as low accuracy due to information loss during molecular representation or incomplete drug feature mining during the training process. Aiming at these problems, this study proposes an accurate and simple framework named PTB-DDI for drug–drug interaction prediction. The PTB-DDI framework consists of four key modules: (1) ChemBerta tokenizer for molecular representation, (2) Bidirectional Long Short-Term Memory (BiLSTM) to capture the bidirectional context-aware features of drugs, (3) Multilayer Perceptron (MLP) for mining the nonlinear relationship of drug features, and (4) interaction predictor to perform an affine transformation and final prediction. In addition, we investigate the effect of dual-mode on parameter-sharing and parameter-independent within the PTB-DDI framework. Furthermore, we conducted comprehensive experiments on the two real-world datasets (i.e., BIOSNAP and DrugBank) to evaluate PTB-DDI framework performance. The results show that our proposed framework has significant improvements over the baselines based on both datasets. Based on the BIOSNAP dataset, the AUC-ROC, PR-AUC, and F1 scores are 0.997, 0.995, and 0.984, respectively. These metrics are 0.896, 0.873, and 0.826 based on the DrugBank dataset. Then, we conduct the case studies on the three newly approved drugs by the Food and Drug Administration (FDA) in 2024 using the PTB-DDI framework in dual modes. The obtained results indicate that our proposed framework has advantages for predicting drug–drug interactions and that the dual modes of the framework complement each other. Furthermore, a free website is developed to enhance accessibility and user experience. Full article

The Module-0 Demonstrator is a single-phase 600 kg liquid argon time projection chamber operated as a prototype for the DUNE liquid argon near detector. Based on the ArgonCube design concept, Module-0 features a novel 80k-channel pixelated charge readout and advanced high-coverage photon detection system. In this paper, we present an analysis of an eight-day data set consisting of 25 million cosmic ray events collected in the spring of 2021. We use this sample to demonstrate the imaging performance of the charge and light readout systems as well as the signal correlations between the two. We also report argon purity and detector uniformity measurements and provide comparisons to detector simulations. Full article

Mammalian cardiomyocytes have limited regenerative ability. Cardiac disease, such as congenital heart disease and myocardial infarction, causes an initial loss of cardiomyocytes through regulated cell death (RCD). Understanding the mechanisms that govern RCD in the injured myocardium is crucial for developing therapeutics to promote heart regeneration. We previously reported that ferroptosis, a non-apoptotic and iron-dependent form of RCD, is the main contributor to cardiomyocyte death in the injured heart. To investigate the mechanisms underlying the preference for ferroptosis in cardiomyocytes, we examined the effects of anti-ferroptotic reagents in infarcted mouse hearts. The results revealed that the anti-ferroptotic reagent did not improve neonatal heart regeneration, and further compromised the cardiac function of juvenile hearts. On the other hand, ferroptotic cardiomyocytes played a supportive role during wound healing by releasing pro-angiogenic factors. The inhibition of ferroptosis in the regenerating mouse heart altered the immune and angiogenic responses. Our study provides insights into the preference for ferroptosis over other types of RCD in stressed cardiomyocytes, and guidance for designing anti-cell-death therapies for treating heart disease. Full article

After more than five decades, Moore’s Law for transistors is approaching the end of the international technology roadmap of semiconductors (ITRS). The fate of complementary metal oxide semiconductor (CMOS) architecture has become increasingly unknown. In this era, 3D transistors in the form of gate-all-around (GAA) transistors are being considered as an excellent solution to scaling down beyond the 5 nm technology node, which solves the difficulties of carrier transport in the channel region which are mainly rooted in short channel effects (SCEs). In parallel to Moore, during the last two decades, transistors with a fully depleted SOI (FDSOI) design have also been processed for low-power electronics. Among all the possible designs, there are also tunneling field-effect transistors (TFETs), which offer very low power consumption and decent electrical characteristics. This review article presents new transistor designs, along with the integration of electronics and photonics, simulation methods, and continuation of CMOS process technology to the 5 nm technology node and beyond. The content highlights the innovative methods, challenges, and difficulties in device processing and design, as well as how to apply suitable metrology techniques as a tool to find out the imperfections and lattice distortions, strain status, and composition in the device structures. Full article

Background and objective: Local advanced rectal cancer (LARC) poses significant treatment challenges due to its location and high recurrence rates. Accurate early detection is vital for treatment planning. With magnetic resonance imaging (MRI) being resource-intensive, this study explores using artificial intelligence (AI) to interpret computed tomography (CT) scans as an alternative, providing a quicker, more accessible diagnostic tool for LARC. Methods: In this retrospective study, CT images of 1070 T3–4 rectal cancer patients from 2010 to 2022 were analyzed. AI models, trained on 739 cases, were validated using two test sets of 134 and 197 cases. By utilizing techniques such as nonlocal mean filtering, dynamic histogram equalization, and the EfficientNetB0 algorithm, we identified images featuring characteristics of a positive circumferential resection margin (CRM) for the diagnosis of locally advanced rectal cancer (LARC). Importantly, this study employs an innovative approach by using both hard and soft voting systems in the second stage to ascertain the LARC status of cases, thus emphasizing the novelty of the soft voting system for improved case identification accuracy. The local recurrence rates and overall survival of the cases predicted by our model were assessed to underscore its clinical value. Results: The AI model exhibited high accuracy in identifying CRM-positive images, achieving an area under the curve (AUC) of 0.89 in the first test set and 0.86 in the second. In a patient-based analysis, the model reached AUCs of 0.84 and 0.79 using a hard voting system. Employing a soft voting system, the model attained AUCs of 0.93 and 0.88, respectively. Notably, AI-identified LARC cases exhibited a significantly higher five-year local recurrence rate and displayed a trend towards increased mortality across various thresholds. Furthermore, the model’s capability to predict adverse clinical outcomes was superior to those of traditional assessments. Conclusion: AI can precisely identify CRM-positive LARC cases from CT images, signaling an increased local recurrence and mortality rate. Our study presents a swifter and more reliable method for detecting LARC compared to traditional CT or MRI techniques. Full article

The Frontline and Relapsed Rhabdomyosarcoma (FaR-RMS) clinical trial is an overarching, multinational study for children and adults with rhabdomyosarcoma (RMS). The trial, developed by the European Soft Tissue Sarcoma Study Group (EpSSG), incorporates multiple different research questions within a multistage design with a focus on (i) novel regimens for poor prognostic subgroups, (ii) optimal duration of maintenance chemotherapy, and (iii) optimal use of radiotherapy for local control and widespread metastatic disease. Additional sub-studies focusing on biological risk stratification, use of imaging modalities, including [¹⁸F]FDG PET-CT and diffusion-weighted MRI imaging (DWI) as prognostic markers, and impact of therapy on quality of life are described. This paper forms part of a Special Issue on rhabdomyosarcoma and outlines the study background, rationale for randomisations and sub-studies, design, and plans for utilisation and dissemination of results. Full article

In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic encephalopathy. The underlying mechanisms are not yet completely clarified. It is well known that portal hypertension causes mesenteric congestion which produces reactive oxygen species (ROS). ROS has been associated with intestinal mucosal injury, increased intestinal permeability, enhanced gut bacterial overgrowth, and translocation; all these changes result in increased endotoxin and inflammation. Portal hypertension also results in the development of collateral circulation and reduces liver mass resulting in an overall increase in endotoxin/bacteria bypassing detoxication and immune clearance in the liver. Endotoxemia can in turn aggravate oxidative stress and inflammation, leading to a cycle of gut barrier dysfunction → endotoxemia → organ injury. The phenotype of cardiovascular abnormalities includes hyperdynamic circulation and cirrhotic cardiomyopathy. Oxidative stress is often accompanied by inflammation; thus, blocking oxidative stress can minimize the systemic inflammatory response and alleviate the severity of cardiovascular diseases. The present review aims to elucidate the role of oxidative stress in cirrhosis-associated cardiovascular abnormalities and discusses possible therapeutic effects of antioxidants on cardiovascular complications of cirrhosis including hyperdynamic circulation, cirrhotic cardiomyopathy, and hepatorenal syndrome. Full article

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of pediatric morbidity and mortality. Young children are at high risk of TB following Mtb exposure, and this vulnerability is secondary to insufficient host immunity during early life. Our primary objective was to compare CD4+ and CD8+ T-cell production of proinflammatory cytokines IFN-gamma, IL-2, and TNF-alpha in response to six mycobacterial antigens and superantigen staphylococcal enterotoxin B (SEB) between Ugandan adults with confirmed TB (n = 41) and young Ugandan children with confirmed (n = 12) and unconfirmed TB (n = 41), as well as non-TB lower respiratory tract infection (n = 39). Flow cytometry was utilized to identify and quantify CD4+ and CD8+ T-cell cytokine production in response to each mycobacterial antigen and SEB. We found that the frequency of CD4+ and CD8+ T-cell production of cytokines in response to SEB was reduced in all pediatric cohorts when compared to adults. However, T-cell responses to Mtb-specific antigens ESAT6 and CFP10 were equivalent between children and adults with confirmed TB. In contrast, cytokine production in response to ESAT6 and CFP10 was limited in children with unconfirmed TB and absent in children with non-TB lower respiratory tract infection. Of the five additional mycobacterial antigens tested, PE3 and PPE15 were broadly recognized regardless of TB disease classification and age. Children with confirmed TB exhibited robust proinflammatory CD4+ and CD8+ T-cell responses to Mtb-specific antigens prior to the initiation of TB treatment. Our findings suggest that adaptive proinflammatory immune responses to Mtb, characterized by T-cell production of IFN-gamma, IL-2, and TNF-alpha, are not impaired during early life. Full article

Effective postoperative analgesia using multimodal approach improves maternal and neonatal outcomes after cesarean delivery. The use of neuraxial approach (local anesthetic and opioids) and intravenous adjunctive drugs, such as nonsteroidal anti-inflammatory drugs and acetaminophen, currently represents the standard regimen for post-cesarean delivery analgesia. Peripheral nerve blocks may be considered in patients who are unable to receive neuraxial techniques; these blocks may also be used as a rescue technique in selected patients. This review discusses the relevant anatomy, current evidence, and advantages and disadvantages of the various peripheral nerve block techniques. Further research is warranted to compare the analgesic efficacy of these techniques, especially newer blocks (e.g., quadratus lumborum blocks and erector spinae plane blocks). Moreover, future studies should determine the safety profile of these blocks (e.g., fascial plane blocks) in the obstetric population because of its increased susceptibility to local anesthetic toxicity. Full article

The microbiome has emerged as a key determinant of human health and reproduction, with recent evidence suggesting a dysbiotic microbiome is implicated in adverse perinatal health outcomes. The existing research has been limited by the sample collection and timing, cohort design, sample design, and lack of data on the preconception microbiome. This prospective, longitudinal cohort study will recruit 2000 Australian women, in order to fully explore the role of the microbiome in the development of adverse perinatal outcomes. Participants are enrolled for a maximum of 7 years, from 1 year preconception, through to 5 years postpartum. Assessment occurs every three months until pregnancy occurs, then during Trimester 1 (5 + 0–12 + 6 weeks gestation), Trimester 2 (20 + 0–24 + 6 weeks gestation), Trimester 3 (32 + 0–36 + 6 weeks gestation), and postpartum at 1 week, 2 months, 6 months, and then annually from 1 to 5 years. At each assessment, maternal participants self-collect oral, skin, vaginal, urine, and stool samples. Oral, skin, urine, and stool samples will be collected from children. Blood samples will be obtained from maternal participants who can access a study collection center. The measurements taken will include anthropometric, blood pressure, heart rate, and serum hormonal and metabolic parameters. Validated self-report questionnaires will be administered to assess diet, physical activity, mental health, and child developmental milestones. Medications, medical, surgical, obstetric history, the impact of COVID-19, living environments, and pregnancy and child health outcomes will be recorded. Multiomic bioinformatic and statistical analyses will assess the association between participants who developed high-risk and low-risk pregnancies, adverse postnatal conditions, and/or childhood disease, and their microbiome for the different sample types. Full article

Large-scale applications of nanotechnology have been extensively studied within the last decade. By exploiting certain advantageous properties of nanomaterials, multifunctional products can be manufactured that can contribute to the improvement of everyday life. In recent years, one such material has been nanocellulose. Nanocellulose (NC) is a naturally occurring nanomaterial and a high-performance additive extracted from plant fibers. This sustainable material is characterized by a unique combination of exceptional properties, including high tensile strength, biocompatibility, and electrical conductivity. In recent studies, these unique properties of nanocellulose have been analyzed and applied to processes related to membrane technology. This article provides a review of recent synthesis methods and characterization of nanocellulose-based membranes, followed by a study of their applications on a larger scale. The article reviews successful case studies of the incorporation of nanocellulose in different types of membrane materials, as well as their utilization in water purification, desalination, gas separations/gas barriers, and antimicrobial applications, in an effort to provide an enhanced comprehension of their capabilities in commercial products. Full article

The quality and starch properties of rice are significantly affected by nitrogen. The effect of the nitrogen application rate (0, 180, and 230 kg ha⁻¹) on the texture of cooked rice and the hierarchical structure and physicochemical properties of starch was investigated over two years using two japonica cultivars, Bengal and Shendao505. Nitrogen application contributed to the hardness and stickiness of cooked rice, reducing the texture quality. The amylose content and pasting properties decreased significantly, while the relative crystallinity increased with the increasing nitrogen rates, and the starch granules became smaller with an increase in uneven and pitted surfaces. The proportion of short-chain amylopectin rose, and long-chain amylopectin declined, which increased the external short-range order by 1045/1022 cm⁻¹. These changes in hierarchical structure and grain size, regulated by nitrogen rates, synergistically increased the setback viscosity, gelatinization enthalpy and temperature and reduced the overall viscosity and breakdown viscosity, indicating that gelatinization and pasting properties were the result of the joint action of several factors. All results showed that increasing nitrogen altered the structure and properties of starch, eventually resulting in a deterioration in eating quality and starch functional properties. A moderate reduction in nitrogen application could improve the texture and starch quality of rice while not impacting on the grain yield. Full article