Evaluation of gellan gum fluid gels as modified release oral liquids

Oral liquids are often preferred for drug administration to patients for whom swallowing is difficult, however formulating modified release versions can be challenging. A potential route to achieve modified release in oral liquids is by using fluid (sheared) gels formed by introducing a shear field during gelation in gel-forming biopolymers. These fluid gels can act as pourable viscoelastic fluids but retain true gel micro/nano structure. Here, we have demonstrated that fluid gels have potential as paediatric oral liquids preventing release of ibuprofen in simulated gastric fluid. Subsequent release at pH 7.4 was affected by the duration of exposure and magnitude of acid pH with a linear relationship between onset of release and the preceding acidic exposure duration. Delayed release was a result of increasing gel stiffness, a consequence of the acidity of the initial release media and exposure time. A much faster release rate was measured when exposure time in acid was 10 min compared with 60 min. This study highlights the potential to design fluid gels that are tuned to have a specified stiffness at a particular pH and exposure time. This could enable the preparation oral liquids with modified release behaviour

Ladder Siamese Network: a Method and Insights for Multi-level Self-Supervised Learning

Siamese-network-based self-supervised learning (SSL) suffers from slow convergence and instability in training. To alleviate this, we propose a framework to exploit intermediate self-supervisions in each stage of deep nets, called the Ladder Siamese Network. Our self-supervised losses encourage the intermediate layers to be consistent with different data augmentations to single samples, which facilitates training progress and enhances the discriminative ability of the intermediate layers themselves. While some existing work has already utilized multi-level self supervisions in SSL, ours is different in that 1) we reveal its usefulness with non-contrastive Siamese frameworks in both theoretical and empirical viewpoints, and 2) ours improves image-level classification, instance-level detection, and pixel-level segmentation simultaneously. Experiments show that the proposed framework can improve BYOL baselines by 1.0% points in ImageNet linear classification, 1.2% points in COCO detection, and 3.1% points in PASCAL VOC segmentation. In comparison with the state-of-the-art methods, our Ladder-based model achieves competitive and balanced performances in all tested benchmarks without causing large degradation in one

CMV infection of trabecular meshwork cells

Purpose: Human cytomegalovirus (HCMV) infections can cause endotheliitis which is associated with an elevation of the intraocular pressure (IOP). However, the mechanism of the IOP elevation has not been determined. The purpose of this study was to determine whether HCMV strains which are capable of infecting corneal endothelial cells can also replicate, induce anti-viral responses, and can reorganize the actin cytoskeleton in trabecular meshwork cells. Study design: Experimental study design Methods: Cultured primary human trabecular meshwork cells (HTMCs) were infected with the Towne or TB40/E strains of HCMV. TB40/E is trophic for vascular endothelial and corneal endothelial cells. Real-time PCR, western blot, and fluorescent immunostaining have been used to determine whether HCMV-infected HTMCs will support the expression of viral mRNA and protein, allow viral replication, and elicit anti-viral host responses. We also determined whether lytic replication was present after an HCMV infection. Results: HCMV infection led to the expression of viral mRNA and proteins of IE1, glycoprotein B(gB), and pp65. TB40/E infection induced interferon-β, a sign of host anti-viral immune response and MCP-1. Together with the induction of the regulators of actin cytoskeleton, myosin phosphatase Rho interacting protein (MPRIP) and monocyte chemotactic protein-1 (MCP-1), TB40/E induced a high level of expression of viral proteins, including IE1, gB, and pp65 as well as actin stress fiber formation, and achieved pathogenically high viral titers. Conclusions: Human trabecular meshwork cells support the replication of endotheliotropic TB40/E strain of HCMV which indicates that this strain may have high virulence for trabecular meshwork

Abi1 gene silencing by short hairpin RNA impairs Bcr-Abl-induced cell adhesion and migration in vitro and leukemogenesis in vivo

Abl interactor (Abi) 1 was first identified as the downstream target of Abl tyrosine kinases and was found to be dysregulated in leukemic cells expressing oncogenic Bcr-Abl and v-Abl. Although the accumulating evidence supports a role of Abi1 in actin cytoskeleton remodeling and growth factor/receptor signaling, it is not clear how it contributes to Bcr-Abl-induced leukemogenesis. We show here that Abi1 gene silencing by short hairpin RNA attenuated the Bcr-Abl-induced abnormal actin remodeling, membrane-type 1 metalloproteinase clustering and inhibited cell adhesion and migration on fibronectin-coated surfaces. Although the knock down of Abi1 expression did not affect growth factor-independent growth of Bcr-Abl-transformed Ba/F3 cells in vitro, it impeded competitive expansion of these cells in non obese diabetic (NOD)/ severe combined immuno-deficiency (SCID) mice. Remarkably, the knock down of Abi1 expression in Bcr-Abl-transformed Ba/F3 cells impaired the leukemogenic potential of these cells in NOD/SCID mice. Abi1 contributes to Bcr-Abl-induced leukemogenesis in part through Src family kinases, as the knock down of Abi1 expression attenuates Bcr-Abl-stimulated activation of Lyn. Together, these data provide for the first time the direct evidence that supports a critical role of Abi1 pathway in the pathogenesis of Bcr-Abl-induced leukemia

The Abl interactor proteins localize to sites of actin polymerization at the tips of lamellipodia and filopodia

AbstractCell movement is mediated by the protrusion of cytoplasm in the form of sheet- and rod-like extensions, termed lamellipodia and filopodia. Protrusion is driven by actin polymerization, a process that is regulated by signaling complexes that are, as yet, poorly defined. Since actin assembly is controlled at the tips of lamellipodia and filopodia [1], these juxtamembrane sites are likely to harbor the protein complexes that control actin polymerization dynamics underlying cell motility. An understanding of the regulation of protrusion therefore requires the characterization of the molecular components recruited to these sites. The Abl interactor (Abi) proteins, targets of Abl tyrosine kinases [2–4], have been implicated in Rac-dependent cytoskeletal reorganization in response to growth factor stimulation [5]. Here, we describe the unique localization of Abi proteins in living, motile cells. We show that Abi-1 and Abi-2b fused to enhanced yellow fluorescent protein (EYFP) are recruited to the tips of lamellipodia and filopodia. We identify the targeting domain as the homologous N terminus of these two proteins. Our findings are the first to suggest a direct involvement of members of the Abi protein family in the control of actin polymerization in protrusion events, and establish the Abi proteins as potential regulators of motility