Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities

The Rho/ROCK pathway is involved in numerous pivotal cellular processes that have made it an area of intense study in cancer medicine, however, Rho-associated coiled-coil containing protein kinase (ROCK) inhibitors are yet to make an appearance in the clinical cancer setting. Their performance as an anti-cancer therapy has been varied in pre-clinical studies, however, they have been shown to be effective vasodilators in the treatment of hypertension and post-ischaemic stroke vasospasm. This review addresses the various roles the Rho/ROCK pathway plays in angiogenesis, tumour vascular tone and reciprocal feedback from the tumour microenvironment and explores the potential utility of ROCK inhibitors as effective vascular normalising agents. ROCK inhibitors may potentially enhance the delivery and efficacy of chemotherapy agents and improve the effectiveness of radiotherapy. As such, repurposing of these agents as adjuncts to standard treatments may significantly improve outcomes for patients with cancer. A deeper understanding of the controlled and dynamic regulation of the key components of the Rho pathway may lead to effective use of the Rho/ROCK inhibitors in the clinical management of cancer

Exploring Affordance and Situated Meaning in Image Captions: A Multimodal Analysis

This paper explores the grounding issue regarding multimodal semantic representation from a computational cognitive-linguistic view. We annotate images from the Flickr30k dataset with five perceptual properties: Affordance, Perceptual Salience, Object Number, Gaze Cueing, and Ecological Niche Association (ENA), and examine their association with textual elements in the image captions. Our findings reveal that images with Gibsonian affordance show a higher frequency of captions containing 'holding-verbs' and 'container-nouns' compared to images displaying telic affordance. Perceptual Salience, Object Number, and ENA are also associated with the choice of linguistic expressions. Our study demonstrates that comprehensive understanding of objects or events requires cognitive attention, semantic nuances in language, and integration across multiple modalities. We highlight the vital importance of situated meaning and affordance grounding in natural language understanding, with the potential to advance human-like interpretation in various scenarios.Comment: 10 pages, 9 figure

Lexical Retrieval Hypothesis in Multimodal Context

Multimodal corpora have become an essential language resource for language science and grounded natural language processing (NLP) systems due to the growing need to understand and interpret human communication across various channels. In this paper, we first present our efforts in building the first Multimodal Corpus for Languages in Taiwan (MultiMoco). Based on the corpus, we conduct a case study investigating the Lexical Retrieval Hypothesis (LRH), specifically examining whether the hand gestures co-occurring with speech constants facilitate lexical retrieval or serve other discourse functions. With detailed annotations on eight parliamentary interpellations in Taiwan Mandarin, we explore the co-occurrence between speech constants and non-verbal features (i.e., head movement, face movement, hand gesture, and function of hand gesture). Our findings suggest that while hand gestures do serve as facilitators for lexical retrieval in some cases, they also serve the purpose of information emphasis. This study highlights the potential of the MultiMoco Corpus to provide an important resource for in-depth analysis and further research in multimodal communication studies

Complex I deficiency due to selective loss of Ndufs4 in the mouse heart results in severe hypertrophic cardiomyopathy.

Mitochondrial complex I, the primary entry point for electrons into the mitochondrial respiratory chain, is both critical for aerobic respiration and a major source of reactive oxygen species. In the heart, chronic dysfunction driving cardiomyopathy is frequently associated with decreased complex I activity, from both genetic and environmental causes. To examine the functional relationship between complex I disruption and cardiac dysfunction we used an established mouse model of mild and chronic complex I inhibition through heart-specific Ndufs4 gene ablation. Heart-specific Ndufs4-null mice had a decrease of ∼ 50% in complex I activity within the heart, and developed severe hypertrophic cardiomyopathy as assessed by magnetic resonance imaging. The decrease in complex I activity, and associated cardiac dysfunction, occurred absent an increase in mitochondrial hydrogen peroxide levels in vivo, accumulation of markers of oxidative damage, induction of apoptosis, or tissue fibrosis. Taken together, these results indicate that diminished complex I activity in the heart alone is sufficient to drive hypertrophic cardiomyopathy independently of alterations in levels of mitochondrial hydrogen peroxide or oxidative damage

Mitochondrial reactive oxygen species are scavenged by Cockayne syndrome B protein in human fibroblasts without nuclear DNA damage

Cockayne syndrome (CS) is a human DNA repair-deficient disease that involves transcription coupled repair (TCR), in which three gene products, Cockayne syndrome A (CSA), Cockayne syndrome B (CSB), and ultraviolet stimulated scaffold protein A (UVSSA) cooperate in relieving RNA polymerase II arrest at damaged sites to permit repair of the template strand. Mutation of any of these three genes results in cells with increased sensitivity to UV light and defective TCR. Mutations in CSA or CSB are associated with severe neurological disease but mutations in UVSSA are for the most part only associated with increased photosensitivity. This difference raises questions about the relevance of TCR to neurological disease in CS. We find that CSB-mutated cells, but not UVSSA-deficient cells, have increased levels of intramitochondrial reactive oxygen species (ROS), especially when mitochondrial complex I is inhibited by rotenone. Increased ROS would result in oxidative damage to mitochondrial proteins, lipids, and DNA. CSB appears to behave as an electron scavenger in the mitochondria whose absence leads to increased oxidative stress. Mitochondrial ROS, however, did not cause detectable nuclear DNA damage even when base excision repair was blocked by an inhibitor of polyADP ribose polymerase. Neurodegeneration in Cockayne syndrome may therefore be associated with ROS-induced damage in the mitochondria, independent of nuclear TCR. An implication of our present results is that mitochondrial dysfunction involving ROS has a major impact on CS-B pathology, whereas nuclear TCR may have a minimal role

Effect of Support Supervision on Maternal and Newborn Health Services and Practices in Rural Eastern Uganda

Background: Support supervision is one of the strategies used to check the quality of services provided at health facilities. From 2013 to 2015, Makerere University School of Public Health strengthened support supervision in the district of Kibuku, Kamuli and Pallisa in Eastern Uganda to improve the quality of maternal and newborn services. Objective: This article assesses quality improvements in maternal and newborn care services and practices during this period. Methods: District management teams were trained for two days on how to conduct the supportive supervision. Teams were then allocated particular facilities, which they consistently visited every quarter. During each visit, teams scored the performance of each facility based on checklists; feedback and corrective actions were implemented. Support supervision focused on maternal health services, newborn care services, human resources, laboratory services, availability of Information, education and communication materials and infrastructure. Support supervision reports and checklists from a total of 28 health facilities, each with at least three support supervision visits, were analyzed for this study and 20 key-informant interviews conducted. Results: There was noticeable improvement in maternal and newborn services. For instance, across the first, second and third quarters, availability of parenteral oxytocin increased from 57% to 75% and then to 82%. Removal of retained products increased from 14% to 50% to 54%, respectively. There was perceived improvement in the use of standards and guidelines for emergency obstetric care and quality of care provided. Qualitatively, three themes were identified that promote the success of supportive supervision: changes in the support supervision style, changes in the adherence to clinical standards and guidelines, and multi-stakeholder engagement. Conclusion: Support supervision helped district health managers to identify and address maternal and newborn service-delivery gaps. However, issues beyond the jurisdiction of district health managers and facility managers may require additional interventions beyond supportive supervision.DFI

Missing Teeth and Restoration Detection Using Dental Panoramic Radiography Based on Transfer Learning With CNNs

Common dental diseases include caries, periodontitis, missing teeth and restorations. Dentists still use manual methods to judge and label lesions which is very time-consuming and highly repetitive. This research proposal uses artificial intelligence combined with image judgment technology for an improved efficiency on the process. In terms of cropping technology in images, the proposed study uses histogram equalization combined with flat-field correction for pixel value assignment. The details of the bone structure improves the resolution of the high-noise coverage. Thus, using the polynomial function connects all the interstitial strands by the strips to form a smooth curve. The curve solves the problem where the original cropping technology could not recognize a single tooth in some images. The accuracy has been improved by around 4% through the proposed cropping technique. For the convolutional neural network (CNN) technology, the lesion area analysis model is trained to judge the restoration and missing teeth of the clinical panorama (PANO) to achieve the purpose of developing an automatic diagnosis as a precision medical technology. In the current 3 commonly used neural networks namely AlexNet, GoogLeNet, and SqueezeNet, the experimental results show that the accuracy of the proposed GoogLeNet model for restoration and SqueezeNet model for missing teeth reached 97.10% and 99.90%, respectively. This research has passed the Research Institution Review Board (IRB) with application number 202002030B0