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Class III Phosphatidylinositol-3 Kinase/Vacuolar Protein Sorting 34 in Cardiovascular Health and Disease
Get PDFPhosphatidylinositol-3 kinases (PI3Ks) play a critical role in maintaining cardiovascular health and the development of cardiovascular diseases (CVDs). Specifically, vacuolar Protein Sorting 34 (VPS34) or PIK3C3, the only member of Class III PI3K, plays an important role in CVD progression. The main function of VPS34 is inducing the production of phosphatidylinositol 3-phosphate, which, together with other essential structural and regulatory proteins in forming VPS34 complexes, further regulates the mammalian target of rapamycin activation, autophagy, and endocytosis. VPS34 is found to have crucial functions in the cardiovascular system, including dictating the proliferation and survival of vascular smooth muscle cells and cardiomyocytes and the formation of thrombosis. This review aims to summarize our current knowledge and recent advances in understanding the function and regulation of VPS34 in cardiovascular health and disease. We also discuss the current development of VPS34 inhibitors and their potential to treat CVDs
The Systemic Side of Disinformation: The Reid Technique as Exploitative Knowledge Production
Get PDFIn this paper, the author analyzes the Reid Technique – the most commonly employed interrogation technique in the United States – to argue that it employs disinformation to reinforce the power and authority of the police while disregarding the harm caused to the individual suspect. Furthermore, the author shows how the Reid Technique reproduces the structural, systemic side of disinformation when false confessions lead to wrongful convictions that codify disinformation as legal precedent. In turn, these wrongful convictions are interpreted as high-quality data that gets incorporated into the fabric of what scholars and members of our society know about crime and justice in America
Digitizing Pre-1978 Dissertations at Binghamton University Libraries
Get PDFIn 2023, Binghamton University Libraries initiated a project to digitize its pre-1978 dissertations and make them available in its institutional repository. This Communication on Practice provides an overview of the key decisions made before embarking on the project, the workflow, and the challenges encountered. We drew upon the experiences and lessons learned from other institutions to guide our process, and hope this paper will serve as a resource for those considering similar projects at their institutions
Potential Pitfalls in Visual Models of Tipping Points - And How to Fix Them
Get PDFVisual models play a crucial role in both science and science communication. However, the distinction between mere analogies and mathematically sound graphical representations is not easy and can be misunderstood not only by laypeople but also within academic literature itself. Moreover, even when the graphical representation exactly corresponds to the mathematical model, its interpretation is often far from obvious. In this paper we discuss the potential landscape visualization commonly used for tipping points in the context of nonlinear dynamics and reveal potential pitfalls, in particular when distinguishing bifurcation induced tipping (B-tipping) from noise-induced tipping (N-tipping).
We propose new visualization techniques for tipping dynamics, carefully distinguishing between B- and N-tipping as well as between single systems and ensembles of systems. Explicitly, we apply these visualizations both to molecular cell biology and to climate science in order to reveal the crucial differences in the interpretation of the visual models. We find that it is crucial to explicitly discuss the assumptions made within the visual model and to be aware of the risk of misinterpretation. These findings apply to a wide range of readership, from graduate students - as some general knowledge of nonlinear systems is required - to research professionals working in the field of nonlinear sciences. This paper provides the theoretical groundwork for these new visualizations. As a next step, we propose to investigate the individual mental models that might be induced by these visualizations using empirical research that builds upon these findings
Internal resonance of a T-shaped electrostatic levitation actuator
Get PDFThis study explores the internal resonance of a T-shaped beam subjected to electrostatic forces at the MEMS scale. The actuator\u27s unique configuration includes a side substrate, a fixed bottom substrate, and a suspended beam, enabling out-of-plane movement when excited. The T-shaped beam is designed to have a commensurate ratio of 1:2 between the fifth and sixth modes. The mathematical model of the system is developed and the shooting method is used to solve the reduced order model. Theoretical and experimental results reveal the interaction of two modes. The results indicate that due to the exchange of energy between the two modes and the quadratic nonlinearity, when the system is excited at the fifth mode, it responds at the sixth mode\u27s resonant frequency. The proposed internal resonator can improve sensitivity in various applications with the great advantages of simplicity and ease of fabrication
Sustainability Hub Newsletter - December 2025
No full textHappy wintertime Bearcats! As we enter the holiday season, consider these ideas about how to make your holidays more sustainable! Along with seed resources to grow indoors despite the cold
Characterization of Site-Specific Q295-Conjugated TLR7 Agonist Immune-Stimulating Antibody Conjugates
No full textRecent advances in immunotherapy as a viable cancer treatment modality has led to the development of immune-stimulating antibody conjugates (ISACs). ISACs are analogous to antibody-drug conjugates (ADCs), which utilize the specificity and stability of an antibody to deliver cytotoxic payloads directly to a tumor. ISACs, however, deliver immune stimulating agents instead, activating adaptive and innate immune responses to engage with tumor cells. Among the various immunostimulants currently being explored, Toll-Like Receptor (TLR) agonists have risen as promising inducers of anti-cancer immune responses. Previously, the Tumey lab has explored ISACs employing an imidazole[4,5-c]quinoline TLR7 agonist with drug-antibody ratios (DAR) of ~8. While induction of the NFκB pathway and tumor regression in mouse models were observed, these ISACs face issues of aggregation, poor pharmacokinetics, heterogeneity, and the inability to employ a recently discovered more potent TLR7 agonist due to aggregation. This is a result of the “Hinge” method used to generate these ISACs, which conjugates linker-payloads to free thiols generated by reducing interchain disulfides of the antibody. In response, a site-specific conjugation method developed by the Tumey lab allows for controlled addition of linker-payloads to a thiolated Q295 site of antibodies. Despite producing DAR 2 conjugates, this “Q295” method offers improved aggregation levels, pharmacokinetics, homogeneity, and the potential for conjugation with the previously unconjugatable potent TLR7 agonist. Herein, this work aims to optimize the Q295 method for generating ISACs employing TLR7 agonists across various antibodies and cleaveable linkers. Additionally, Q295 conjugates are characterized and evaluated against their Hinge conjugate counterparts in a variety of co-culture models for NF-κB activation and IL-6 release, as well as lysosomal payload release assays to elucidate possible differences in release mechanisms affecting efficacy
Dissecting the Efficacy and Immunogenicity of TLR7 Agonist–Antibody Conjugates through the Lens of Fc Effector Function, Conjugation Strategies, and Linker Cleavability
No full textThe advent of immuno-oncology therapeutics has given rise to antibody-drug conjugates (ADC) designed to selectively activate pattern recognition receptors such as Toll-Like Receptors (TLRs). In contrast to classical ADC technology, these Immune Stimulating Antibody Conjugates (ISACs) are widely reported to rely on Fcγ-mediated uptake and noncleavable linkers. Herein, we systematically study the impact of Fc effector function, linker cleavability, and conjugation strategy on the efficacy and immunogenicity of a series of TLR7 agonist-based ISACs. We demonstrate that the combination of FcγR-ablation and incorporation of a cleavable linker results in increased stimulation of myeloid cells, enhanced efficacy, and improved tolerability as compared to traditional ISAC designs. Interestingly, we found that all ISAC designs exhibited evidence of antidrug-antibody (ADA) induction. We found that the combination of a cleavable linker, a highly permeable TLR7 agonist payload, and ablation of FcγR binding results in ISACs that exhibit particularly favorable properties for continued development
The Impact of Substance Use Disorder and Drug Transfer into Breast Milk: Implications for Maternal and Infant Health
Get PDFBreast milk provides significant health benefits to both infants and mothers, offering protection against infections and enhancing cognitive development. This paper examines the complex effects of substance use disorder (SUD) during pregnancy and lactation, focusing on the pharmacokinetics of drug transfer into breast milk. It highlights the mechanisms by which drugs enter milk, emphasizing the roles of passive diffusion and active transport, particularly through breast cancer resistance protein (BCRP). The study explores the impact of various substances on fetal and infant health, with a focus on the relative infant dose (RID) and milk-to-plasma (MP) ratio as key metrics for assessing drug safety in breastfeeding. The findings underscore the need for careful evaluation of maternal drug use during lactation to balance the benefits of breastfeeding with potential risks