BET Inhibition-Induced GSK3β Feedback Enhances Lymphoma Vulnerability to PI3K Inhibitors

The phosphatidylinositol 3 kinase (PI3K)-glycogen synthase kinase \u3b2 (GSK3\u3b2) axis plays a central role in MYC-driven lymphomagenesis, and MYC targeting with bromodomain and extraterminal protein family inhibitors (BETi) is a promising treatment strategy in lymphoma. In a high-throughput combinatorial drug screening experiment, BETi enhance the antiproliferative effects of PI3K inhibitors in a panel of diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma cell lines. BETi or MYC silencing upregulates several PI3K pathway genes and induces GSK3\u3b2 S9 inhibitory phosphorylation, resulting in increased \u3b2-catenin protein abundance. Furthermore, BETi or MYC silencing increases GSK3\u3b2 S9 phosphorylation levels and \u3b2-catenin protein abundance through downregulating the E2 ubiquitin conjugating enzymes UBE2C and UBE2T. In a mouse xenograft DLBCL model, BETi decrease MYC, UBE2C, and UBE2T and increase phospho-GSK3\u3b2 S9 levels, enhancing the anti-proliferative effect of PI3K inhibitors. Our study reveals prosurvival feedbacks induced by BETi involving GSK3\u3b2 regulation, providing a mechanistic rationale for combination strategies. In this study, Derenzini et al. demonstrate that BET inhibitors enhance lymphoma vulnerability to PI3K inhibitors by inducing GSK3\u3b2 feedback in a MYC-dependent manner and by downregulating E2-ubiquitin conjugating enzymes, which further enhance the feedback. These data provide the rationale for combining BET and PI3K inhibitors in lymphoma therapy

Facile Preparation of Fluorescent Neoglycoproteins Using p-Nitrophenyl Anthranilate as a Heterobifunctional Linker

A facile preparation of neoglycoconjugates has been developed with a commercially available chemical, p-nitrophenyl anthranilate (PNPA), as a heterobifunctional linker. The two functional groups of PNPA, the aromatic amine and the p-nitrophenyl ester, are fully differentiated to selectively conjugate with glycans and other biomolecules containing nucleophiles. PNPA is efficiently conjugated with free reducing glycans via reductive amination. The glycan−PNPA conjugates (GPNPAs) can be easily purified and quantified by UV absorption. The active p-nitrophenyl ester in the GPNPA conjugates readily reacts with amines under mild conditions, and the resulting conjugates acquire strong fluorescence. This approach was used to prepare several fluorescent neoglycoproteins. The neoglycoproteins were covalently printed on activated glass slides and were bound by appropriate lectins recognizing the glycans

Modern microwave methods in solid state inorganic materials chemistry: from fundamentals to manufacturing

No abstract available

Modelling climate and societal resilience in the Eastern Mediterranean in the last Millennium

This article analyses high-quality hydroclimate proxy records and spatial reconstructions from the Central and Eastern Mediterranean and compares them with two Earth System Model simulations (CCSM4, MPI-ESM-P) for the Crusader period in the Levant (1095–1290 CE), the Mamluk regime in Transjordan (1260–1516 CE) and the Ottoman crisis and Celâlî Rebellion(1580–1610 CE). During the three time intervals, environmental and climatic stress tested the resilience of complex societies.We find that the multidecadal precipitation and drought variations in the Central and Eastern Mediterranean cannot be explained by external forcings (solar variations, tropical volcanism); rather they were driven by internal climate dynamics. Our research emphasises the challenges, opportunities and limitations of linking proxy records, palaeoreconstructions and model simulations to better understand how climate can affect human history

Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition

Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb’s cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4′-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT. Killing of Mtb by the compound is potentiated by another enzyme encoded in the same operon, Ppt hydrolase (PptH), that undoes the PptT reaction. Thus, loss-of-function mutants of PptH displayed antimicrobial resistance. Our PptT-inhibitor cocrystal structure may aid further development of antimycobacterial agents against this long-sought target. The opposing reactions of PptT and PptH uncover a regulatory pathway in CoA physiology

Chemical Approaches To Perturb, Profile, and Perceive Glycans

Glycosylation is an essential form of post-translational modification that regulates intracellular and extracellular processes. Regrettably, conventional biochemical and genetic methods often fall short for the study of glycans, because their structures are often not precisely defined at the genetic level. To address this deficiency, chemists have developed technologies to perturb glycan biosynthesis, profile their presentation at the systems level, and perceive their spatial distribution. These tools have identified potential disease biomarkers and ways to monitor dynamic changes to the glycome in living organisms. Still, glycosylation remains the underexplored frontier of many biological systems. In this Account, we focus on research in our laboratory that seeks to transform the study of glycan function from a challenge to routine practice